View source for Chemistry:List of cocaine analogues

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{{multiple image
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 | footer = '''Top:''' Cocaine in the chair conformation of the tropane-ring, with only its tropane locants given.<br><br>'''Middle:''' Cocaine with its numerical substitution position [[Chemistry:Locant|locant]]s.<br>'''2′''' ('''6′''') = ''ortho'', '''3′''' ('''5′''') = ''meta'' & '''4′''' = ''para''<br><br>'''Bottom:''' Alternate two-dimensional molecular diagram of cocaine; shown specifically as a [[Chemistry:Protonation|protonated]], NH+, [[Chemistry:Hydrochloride|hydrochloride]], and disregarding 3D stereochemistry
 | image1 = Cocaine positions tropane-ring only.png
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This is a list of [[Biology:Cocaine|cocaine]] [[Chemistry:Derivative|analogues]]. A '''cocaine analogue''' is an (usually) artificial construct of a novel [[Chemistry:Chemical compound|chemical compound]] from (often the starting point of natural) cocaine's molecular structure, with the result product sufficiently similar to cocaine to display similarity in, but alteration to, its chemical function. Within the scope of analogous compounds created from the structure of cocaine, so named "cocaine analogues" retain 3''β''-benzoyloxy or similar functionality (the term specifically used usually distinguishes from [[Chemistry:Phenyltropane|phenyltropane]]s, but in the broad sense generally, as a category, includes them) on a tropane skeleton, as compared to other stimulants of the kind. Many of the semi-synthetic cocaine analogues ''proper'' which have been made & studied have consisted of among the nine following classes of compounds:{{efn|<ref name="Singh2">{{cite journal | last1 = Singh | first1 = Satendra |display-authors=0  | year = 2000 | title = Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists | url = https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf | journal = Chem. Rev. | volume = 100 | issue = 3| pages = 925–1024 | doi=10.1021/cr9700538 | pmid=11749256}}</ref> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#45 Page #969 (45th page of article)] §III. ¶1. Final line. Last sentence.}}
* stereoisomers of cocaine
* 3''β''-phenyl ring substituted analogues
* 2''β''-substituted analogues
* ''N''-modified analogues of cocaine
* 3''β''-carbamoyl analogues
* 3''β''-alkyl-3-benzyl tropanes
* 6/7-substituted cocaines
* 6-alkyl-3-benzyl tropanes
* piperidine homologues of cocaine

However strict analogues of cocaine would also include such other potential combinations as phenacyltropanes & other carbon branched replacements not listed above. The term may also be loosely used to refer to drugs manufactured from cocaine or having their basis as a [[Chemistry:Total synthesis|total synthesis]] of cocaine, but modified to alter their effect & [[Chemistry:Quantitative structure–activity relationship|QSAR]]. These include both intracellular sodium channel blocker anaesthetics and stimulant [[Chemistry:Dopamine reuptake inhibitor|dopamine reuptake inhibitor]] [[Chemistry:Ligand|ligand]]s (such as certain, namely tropane-bridged-excised, [[Chemistry:Piperidine|piperidine]]s). Additionally, researchers have supported combinatorial approaches for taking the most promising analogues currently elucidated and mixing them to the end of discovering novel & efficacious compounds to optimize their utilization for differing distinct specified purposes.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#94 Page #1,018 (94th page of article) 2nd column, 2nd paragraph.]}}

==[[Chemistry:Structural analog#Chemistry|Analogs ''sensu stricto'']]==

===Cocaine Stereoisomers===
{| class="wikitable" style = "float: center; margin-left:15px; text-align:center"
! Structure
! Stereoisomer
! S. Singh's<br>alphanumeric<br>assignation
! [[Chemistry:IC50|IC<sub>50</sub>]] ([[Mole (unit)#Related units|nM]])<br>[[Physics:Tritium|[<sup>3</sup>H]]]WIN 3542 inhibition to <br>rat [[Biology:Striatum|striatal]] membranes<br><small>Mean error standard ≤5% in all cases</small>
! [[Chemistry:Chemical nomenclature|IUPAC<br>nomenclature]]
|-
|[[File:R-cocaine.svg|x100px]] 
|[[Biology:Cocaine|''R''-cocaine]]<br>(Erythroxyline)
| 
| 102
| methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
|-
| [[File:R-pseudococaine.svg|x110px]]
| ''R''-pseudococaine<br>(Delcaine, Depsococaine, Dextrocaine, Isococaine, Psicaine.<ref>{{cite journal | pmid = 20771843 | pmc=2196615 | volume=1 |issue = 3340| year=1925 | journal=Br Med J | pages=11 | last1 = Watson-Williams | first1 = E | title=Psicaine: An Artificial Cocaine | doi=10.1136/bmj.1.3340.11}}</ref>)
| 172
| 15800
| methyl(1R,'''2S''',3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
|-
| | [[File:R-allococaine.svg|x110px]]
| ''R''-allococaine
| 173
| 6160
| methyl(1R,2R,'''3R''',5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
|-
| [[File:R-allopseudococaine.svg|x110px]]
| ''R''-allopseudococaine
| 174
| 28500
| methyl(1R,'''2S''','''3R''',5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
|-
| [[File:S-cocaine.svg|x100px]]
| ''S''-cocaine
| 175
| 15800
| methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-'''4'''-carboxylate
|-
| [[File:S-pseudococaine.svg|x100px]]
| ''S''-pseudococaine
| 176
| 22500
| methyl(1S,3R,'''4S''',5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-'''4'''-carboxylate
|-
| [[File:S-allococaine.svg|x110px]]
| ''S''-allococaine
| 177
| 9820
| methyl(1S,'''3S''',4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-'''4'''-carboxylate
|-
| [[File:S-allopseudococaine.svg|x110px]]
| ''S''-allopseudococaine
| 178
| 67700
| methyl(1S,'''3S''','''4S''',5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-'''4'''-carboxylate
|-
|}
[[File:Cocaine Pharmacophore.svg|thumb|x180px|The structure of cocaine with relevant structural motifs for activity at the [[Biology:Dopamine transporter|dopamine transporter]] highlighted. <br><br><small>While it was originally thought that the 2β-carbomethoxy moiety interacted with the DAT through hydrogen bonding, subsequent research has indicated that electrostatic (ionic) interactions are the primary means of interactions with the DAT.</small>{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#16 Page #940 (16th page of article) underneath Table 8., above §4]}}]]
There are eight [[Chemistry:Stereoisomerism|stereoisomers]] of cocaine (excluding [[Chemistry:Resonance|mesomers]] and modifications to the internal portion of the tropane ring).{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#46 Page #970 (46th page of article)] Table 27. Figure 29.}} Due to the presence of four asymmetric carbon atoms in the 1- & 5- to 8 (N) position bond bridge that could adopt ''R-'' & ''S-'' configurations, cocaine can be considered to have as many as sixteen stereoisomers. However, geometric constraints imparted by the bridgehead amine allow only eight to be created. 

The natural isomerism of cocaine is unstable and prone to [[Chemistry:Epimer|epimer]]ization. For example, the end product of cocaine biosynthesis contains an axial C2-carbomethoxy moiety which readily undergoes [[Chemistry:Epimer|epimer]]ization to the equatorial position via [[Chemistry:Saponification|saponification]].

For any 2D structural diagrams where stereochemistry is not indicated, it should be assumed the analogue depicted shares the stereochemical conformation of ''R''-cocaine unless noted otherwise.
<br>
===[[Chemistry:Aromatic hydrocarbon|Arene benzene-ring]] 2′, 3′, 4′ (5′ & 6′) position ([[Chemistry:Aryl|aryl]]) substitutions===

====''para''-substituted benzoylmethylecgonines====
{| class="wikitable sortable"
|+Carbon 4′-hydrogen Substitutions ([[Chemistry:Benzene|benzene]]-4′ "''para''" substituted benzoyloxytropanes){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30. & Page #973 (49th page of article) Table 28.}}<br><sup>Data-set congruent to, and aggregate with, following tables<br>IC<sub>50</sub> values</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! 4′=[[Chemistry:Side chain|R]]
! DAT
[<sup>3</sup>H]WIN 35428
! 5-HTT
[<sup>3</sup>H]Paroxetine
! NET
[<sup>3</sup>H]Nisoxetine
! Selectivity
5-HTT/DAT
! Selectivity
NET/DAT
|-
| ||Cocaine||[[Chemistry:Hydrogen|H]]||249 ± 37||615 ± 120||2500 ± 70||2.5||10.0
|-
|''non-benzoyloxy analogue<br>comparative ligands''<br>{{smallsub|''non-tropane analogue<br>comparative ligands''}}||11b (WIN 35428)<small><br><sub>(nisoxetine)</sub><br><sup>(fluoxetine)</sup></small>||[[Chemistry:Fluorine|F]]<small><br><sub>—</sub><br><sup>—</sup></small>||24 ± 4<small><br><sub>775 ± 20</sub><br><sup>5200 ± 1270</sup></small>||690 ± 14<small><br><sub>762 ± 90</sub><br><sup>15 ± 3</sup></small>||258 ± 40<small><br><sub>135 ± 21</sub><br><sup>963 ± 158</sup></small>||28.7<small><br><sub>1.0</sub><br><sup>0.003</sup></small>||10.7<small><br><sub>0.2</sub><br><sup>0.2</sup></small>
|-
|rowspan=7|[[File:183a-d Scaffold.svg|200px|Satendra Singh Rev]]
|-
| 183a || [[Chemistry:Iodine|I]] ||2522 ± 4||1052 ± 23||18458 ± 1073||0.4||7.3
|-
| 183b || [[Chemistry:Phenyl group|Ph]] ||486 ± 63|| - || - || - || -
|-
| 183c || [[Chemistry:Acetoxy group|OAc]] ||144 ± 2|| - || - || - || -
|-
| 183d || OH ||158 ± 8||3104 ± 148||601 ± 11||19.6||3.8
|-
| ([[Chemistry:4′-Fluorococaine|4′-Fluorococaine]])<ref name="pmid8113802">{{cite journal |vauthors=Gatley SJ, Yu DW, Fowler JS, MacGregor RR, Schlyer DJ, Dewey SL, Wolf AP, Martin T, Shea CE, Volkow ND |title=Studies with differentially labeled [11C]cocaine, [11C]norcocaine, [11C]benzoylecgonine, and [11C]- and 4′-[18F]fluorococaine to probe the extent to which [11C]cocaine metabolites contribute to PET images of the baboon brain |journal=Journal of Neurochemistry |volume=62 |issue=3 |pages=1154–62 |date=March 1994 |pmid=8113802 |doi= 10.1046/j.1471-4159.1994.62031154.x|s2cid=25854431 }}</ref> || [[Chemistry:Fluorine|F]] || - || - || - || - || -
|-
| ([[Chemistry:(R)-p-Isothiocyanatobenzoylecgonine methyl ester|''para''-Isothiocyanatobenzoylecgonine<br>methyl ester]])<ref>{{cite journal |title= Cocaine Receptor: Biochemical Characterization and Structure-Activity Relationships of Cocaine Analogues at Dopamine Transporter |author1=Carroll, F. I. |author2=Lewin, A. H. |author3=Boja, J. W. |author4=Kuhar, M. J. |journal= Journal of Medicinal Chemistry |volume= 35 |issue= 6 |year= 1992 |pages= 969–981 |doi= 10.1021/jm00084a001 |pmid=1552510}}</ref><br>([[Chemistry:Arene substitution pattern#Ortho, meta, and para substitution|''p'']]-Isococ) || [[Chemistry:Isothiocyanate|NCS]] || - || - || - || - || -
|}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | ''para''-substituted benzoylmethylecgonines
|-
! 183a !! 183b !! 183c
|-
| [[File:Cocaine analog 183a.svg|x150px]] || x150px || [[File:Cocaine analog 183c.svg|x150px]]
|-
! 183d !! 4'-Fluorococaine !! [[Chemistry:(R)-p-Isothiocyanatobenzoylecgonine methyl ester|P-ISOCOC]]
|-
| [[File:Cocaine analog 183d.svg|x150px]] || x170px || [[File:P-ISOCOC.svg|x140px]]
|}
The [[Biology:Monoamine transporter|MAT]] [[Biology:Active site#Binding site|binding pocket]] analogous to the lipophilic place on cocaine-like compounds, inclusive of the benzene ring, is approximate to 9 [[Angstrom|Å]] in length. Which is only slightly larger than a phenyl ring by itself.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)]}}

====''meta''-substituted benzoylmethylecgonines====
{| class="wikitable sortable"
|+Carbon 3′-hydrogen Substitutions (benzene-3′ "''meta''" substituted benzoyloxytropanes){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30 & Page #971 (47th page of article) Figure 30 & [https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973] (49th page of article) Table 28}}<br><sup>Data-set congruent to, and aggregate with, preceding and following tables<br>IC<sub>50</sub> values</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! 3′=R
! DAT
[<sup>3</sup>H]WIN 35428
! 5-HTT
[<sup>3</sup>H]Paroxetine
! NET
[<sup>3</sup>H]Nisoxetine
! Selectivity
5-HTT/DAT
! Selectivity
NET/DAT
|-
| ||(cocaine)||[[Chemistry:Hydrogen|H]]||249 ± 37||615 ± 120||2500 ± 70||2.5||10.0
|-
|-
|rowspan=5|[[File:184a-b Scaffold.svg|200px|Satendra Singh Rev]]
|-
| 184a || I ||325<sup>'''ɑ'''</sup>|| - || - || - || -
|-
| 184b || OH ||1183 ± 115||793 ± 33||3760 ± 589||0.7||3.2
|-
| 191 || OBn || - || - || - || - || -
|-
| ([[Chemistry:Arene substitution pattern#Ortho, meta, and para substitution|''m'']]-Isococ) || [[Chemistry:Isothiocyanate|NCS]] || - || - || - || - || -
|}
*<sup>'''ɑ'''</sup><small>IC<sub>50</sub> value for displacement of [<sup>3</sup>H]cocaine</small>
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | ''meta''-substituted benzoylmethylecgonines
|-
! 184a !! 184b !! m-ISOCOC !! C3-Benzyloxycocaine
|-
| [[File:Cocaine analog 184a.svg|x140px]] || x140px || x140px ||[[File:C3benzyloxycocaine.svg|x150px]]
|- 
|}

====''ortho''-substituted benzoylmethylecgonines====
{| class="wikitable sortable"
|+Carbon 2′-hydrogen Substitutions (benzene-2′ "''ortho''" substituted benzoyloxytropanes){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30 & Page #971 (47th page of article) Figure 30 & [https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973] (49th page of article) Table 28}}<br><sup>Data-set congruent to, and aggregate with, preceding and following tables<br>IC<sub>50</sub> values</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! 2′=R
! DAT
[<sup>3</sup>H]WIN 35428
! 5-HTT
[<sup>3</sup>H]Paroxetine
! NET
[<sup>3</sup>H]Nisoxetine
! Selectivity
5-HTT/DAT
! Selectivity
NET/DAT
|-
| ||Cocaine||[[Chemistry:Hydrogen|H]]||249 ± 37||615 ± 120||2500 ± 70||2.5||10.0
|-
|-
|rowspan=5|[[File:185a-d Scaffold.svg|200px|Satendra Singh Rev]]
|-
| 185a || I ||350<sup>'''ɑ'''</sup>|| - || - || - || -
|-
| 185b || F ||604 ± 67||1770 ± 309||1392 ± 173||2.9||2.3
|-
| 185c<br>([[Chemistry:2′-Acetoxycocaine|2′-Acetoxycocaine]])<ref>{{cite journal | pmid = 9427328 | year = 1997 | last1 = Seale | first1 = TW | last2 = Avor | first2 = K | last3 = Singh | first3 = S | last4 = Hall | first4 = N | last5 = Chan | first5 = HM | last6 = Basmadjian | first6 = GP | title = 2′-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding | volume = 8 | issue = 16 | pages = 3571–5 | journal = NeuroReport | doi=10.1097/00001756-199711100-00030| s2cid = 24348794 }}</ref> || OAc ||70 ± 1||219 ± 20||72 ± 9||3.1||1.0
|-
| 185d<br>([[Chemistry:Salicylmethylecgonine|2′-Hydroxycocaine]])<ref name=Salicyl>{{cite journal | last1 = Singh | first1 = S | last2 = Basmadjian | first2 = GP | last3 = Avor | first3 = K | last4 = Pouw | first4 = B | last5 = Seale | first5 = TW | year = 1997 | title = A convenient synthesis of 2?- or 4?-hydroxycocaine | url = https://www.scribd.com/doc/39496623/salicylmethylecgonine | journal = Synthetic Communications | volume = 27 | issue = 22| pages = 4003–4012 | doi = 10.1080/00397919708005923 }}<br>et. {{cite journal | last1 = el-Moselhy | first1 = TF | last2 = Avor | first2 = KS | last3 = Basmadjian | first3 = GP | date = Sep 2001 | title = 2?-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies | journal = Archiv der Pharmazie | volume = 334 | issue = 8–9| pages = 275–8 | pmid = 11688137 | doi = 10.1002/1521-4184(200109)334:8/9<275::aid-ardp275>3.0.co;2-b | s2cid = 41556606 }}<br> et. {{cite journal | last1 = Seale | first1 = TW | last2 = Avor | first2 = K | last3 = Singh | first3 = S | last4 = Hall | first4 = N | last5 = Chan | first5 = HM | last6 = Basmadjian | first6 = GP | year = 1997 | title = 2?-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding | journal = NeuroReport | volume = 8 | issue = 16| pages = 3571–5 | pmid = 9427328 | doi = 10.1097/00001756-199711100-00030 | s2cid = 24348794 }}</ref> || OH ||25 ± 4||143 ± 21||48 ± 2||5.7||1.9
|}
*<sup>'''ɑ'''</sup><small>IC<sub>50</sub> value for displacement of [<sup>3</sup>H]cocaine</small>
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | ''ortho''-substituted benzoylmethylecgonines
|-
! 185a !! 185b !! 185c !! 185d
|-
| [[File:Cocaine analog 185a.svg|x150px]] || x150px || x150px || [[File:Cocaine analog 185d.svg|x150px]]
|}
The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#48 Page #972 (48th page of article)] ¶2, Line 10.}}

====Manifold and termination benzoyloxy phenyl-substitutions====

{| class="wikitable"
|-
! [[Chemistry:Methylvanillylecgonine|Vanillylmethylecgonine]] !! 186b 
|-
| [[File:Hydroxymethoxycocaine.svg|x150px]] || [[File:Cocaine analog 186.svg|x150px]] 
|}

Multi-substitutions (substitutions of substitutions; e.g. [[Chemistry:Arene substitution pattern#Ortho, meta, and para substitution|''meta''- & ''para''-]]) or manifold ("many-fold") substituted analogues are analogues where more than one modification from the parent molecule takes place (having numerous intermediary constituents). These are created with often surprising structure–activity relationship results extrapolated therefrom. It is even a common case where two separate substitutions can each yield a weaker, lower affinity or even wholly non-efficacious compound respectively; but due to findings that oftentimes, when used together, such two mutually inferior changes being added in tandem to one analogue has the potential to make the resultant derivative display much greater efficacy, affinity, selectivity &/or strength than even the parent compound; which otherwise was compromised by either of those two alternations when made alone.

{| class="wikitable sortable"
|+Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple benzene-2′,3′ & 4′ combined substituted benzoyloxytropanes){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30 & Page #971 (47th page of article) Figure 30 & [https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973] (49th page of article) Table 28}}<br><sup>Data-set (excepting instanced references inside table) congruent to, and aggregate with, preceding and following tables<br>IC<sub>50</sub> values</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''ortho''-2′=''R''
! ''meta''-3′=''R''
! ''para''-4′=''R''
! DAT
[<sup>3</sup>H]WIN 35428
! 5-HTT
[<sup>3</sup>H]Paroxetine
! NET
[<sup>3</sup>H]Nisoxetine
! Selectivity
5-HTT/DAT
! Selectivity
NET/DAT
|-
| [[File:Cocaine analog 186.svg|x150px]] || 186 || HO || H || I ||215 ± 19||195 ± 10||1021 ± 75||0.9||4.7
|-
| [[File:Hydroxymethoxycocaine.svg|x70px]] || ([[Chemistry:Methylvanillylecgonine|Vanillylmethylecgonine]])<ref name=Vanillyl>{{cite journal | year = 1984 | title = Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine | pmid = 6708474 | journal = Journal of Analytical Toxicology | volume = 8 | issue = 1| pages = 29–34  | last1 = Smith | first1 = RM | last2 = Poquette | first2 = MA | last3 = Smith | first3 = PJ | doi=10.1093/jat/8.1.29}}</ref> || H || OCH<sub>3</sub> || OH || - || - || - || - || -
|}

{| class="wikitable sortable"
|+Terminating Phenyl Carbon Ring Fusions & Alterations{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30 & Page #971 (47th page of article) Figure 30 & [https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973] (49th page of article) Table 28}}<br><sup>Data-set congruent to, and aggregate with, preceding table<br>IC<sub>50</sub> values</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! C=''R''
! DAT
[<sup>3</sup>H]Cocaine (IC<sub>50</sub>)
|-
| [[File:Cocaine analog 187.svg|x150px]] || 187 || 1-naphthalene ||742 ± 48
|-
| [[File:Cocaine analog 188.svg|x150px]] || 188 || 2-naphthalene ||327 ± 63
|}

===Benzoyl and carbomethoxy branch modifications===
 {{multiple image
 | direction = vertical
 | image1 = Spirocyclic cocaine analog.svg
 | width1 = 220
 | caption1 = Spirocyclic benzoyl branch modification that fits criteria as a cocaine analog and a phenyltropane both (tropane 2nd locant ester rendered in given depiction shows, as has been attested, to only having been successfully alpha configured)<ref>{{cite journal | last1 = Sakamuri | first1 = Sukumar |display-authors=0  | year = 2000 | title = Synthesis of novel spirocyclic cocaine analogs using the Suzuki coupling | journal = Tetrahedron Letters | volume = 41 | issue = 13| pages = 2055–2058 | doi = 10.1016/S0040-4039(00)00113-1 }}</ref>
 | image2 = Spirocyclic_cocaine_analog_12.svg
 | width2 = 220
 }}
* [[Chemistry:Benzoylthiomethylecgonine|Benzoylthiomethylecgonine]]<ref>{{cite journal | last1 = Isomura | first1 = Shigeki | last2 = Hoffman | first2 = Timothy Z. | last3 = Wirsching | first3 = Peter | last4 = Janda | first4 = Kim D. | year = 2002 | title = Benzoylthio-. cocaine, analogue substitution. Synthesis, Properties, and Reactivity of Cocaine Benzoylthio Ester Possessing the Cocaine Absolute Configuration | journal = J. Am. Chem. Soc. | volume = 124 | issue = 14| pages = 3661–3668 | doi = 10.1021/ja012376y | pmid=11929256}}</ref>

[[File:Benzoylthiomethylecgonine.svg|x150px]]<br>
A sulfur in place of the oxygen at the benzoyl ester single bond results in a lower electronegativity than that of cocaine.

* [[Chemistry:Cocaine reverse ester|Cocaine reverse ester (REC)]]<ref name="pmid5031343">{{cite journal | vauthors = Daum SJ, Martini CM, Kullnig RK, Clarke RL | title = Compounds affecting the central nervous system. I. Tropane-2 ,3 -diol derivatives. A reverse ester of cocaine | journal = The Journal of Organic Chemistry | volume = 37 | issue = 10 | pages = 1665–9 | date = May 1972 | pmid = 5031343 | doi = 10.1021/jo00975a045 }}</ref>

[[File:REC_structure.png|x150px]]<br>
REC is a cocaine analogue which contains a "reversed" C2 carbomethoxy moiety. In animal studies, REC lacked cocaine-like stimulant effects.

===C1-tropane-ring hydrogen—substitutions===
{| class="wikitable sortable"
|+C1 substitutions<ref name="DavisGaddiraju2012">{{cite journal|last1=Davis|first1=Franklin A.|last2=Gaddiraju|first2=Narendra V.|last3=Theddu|first3=Naresh|last4=Hummel|first4=Joshua R.|last5=Kondaveeti|first5=Sandeep K.|last6=Zdilla|first6=Michael J.|title=Enantioselective Synthesis of Cocaine C-1 Analogues using Sulfinimines (N-Sulfinyl Imines)|journal=The Journal of Organic Chemistry|volume=77|issue=5|year=2012|pages=2345–2359|issn=0022-3263|doi=10.1021/jo202652f|pmid=22300308|url=https://figshare.com/articles/Enantioselective_Synthesis_of_Cocaine_C_1_Analogues_using_Sulfinimines_i_N_i_Sulfinyl_Imines_/2544925}}</ref><small><br>''K''<sub>i</sub> values for uptake inhibition obtained on HEK-293 heterologously expressed human monoamine transporter cells.</small><ref name="ReithAli2012">{{cite journal|last1=Reith|first1=M. E. A.|last2=Ali|first2=S.|last3=Hashim|first3=A.|last4=Sheikh|first4=I. S.|last5=Theddu|first5=N.|last6=Gaddiraju|first6=N. V.|last7=Mehrotra|first7=S.|last8=Schmitt|first8=K. C.|last9=Murray|first9=T. F.|last10=Sershen|first10=H.|last11=Unterwald|first11=E. M.|last12=Davis|first12=F. A.|title=Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine|journal=Journal of Pharmacology and Experimental Therapeutics|volume=343|issue=2|year=2012|pages=413–425|issn=1521-0103|doi=10.1124/jpet.112.193771|pmid=22895898|pmc=3477221}} [http://jpet.aspetjournals.org/content/343/2/413.full.pdf#page=1&view=FitH Full article]</ref>
! Structure
! Trivial name
! ''R''<br>(C1 moiety)
! ''K''<sub>i</sub> (''nM'') @ DAT
! ''K''<sub>i</sub> (''nM'') @ SERT
! ''K''<sub>i</sub> (''nM'') @ NET
! σ<sub>1</sub> affinity<br>''K''<sub>i</sub>
! σ<sub>2</sub> affinity<br>''K''<sub>i</sub>
! IC<sub>50</sub> (μM) Na+ inhibition<br>(Vertridine-Stimulated<br>influx of sodium channels<br>in Neocortical neurons)<sup>'''c'''</sup>
! LogP<br>(XLogP3 algorithm, Cheng et al., 2007)
|-
| || (—)-Cocaine || H ||326 ± 106||513 ± 143||358 ± 69||6.7 ± 0.3 μM'''<sup>d</sup>'''<ref>{{cite journal | pmid = 2840298 | volume=149 | issue=1–2 | title=Cocaine binding at sigma receptors | journal=Eur J Pharmacol | pages=171–4 | last1 = Sharkey | first1 = J | last2 = Glen | first2 = KA | last3 = Wolfe | first3 = S | last4 = Kuhar | first4 = MJ | doi = 10.1016/0014-2999(88)90058-1 | year=1988 }}</ref>||"significant"<ref name="NuwayhidWerling2006">{{cite journal|last1=Nuwayhid|first1=Samer J.|last2=Werling|first2=Linda L.|title=Sigma2 (σ2) receptors as a target for cocaine action in the rat striatum|journal=European Journal of Pharmacology|volume=535|issue=1–3|year=2006|pages=98–103|issn=0014-2999|doi=10.1016/j.ejphar.2005.12.077|pmid=16480713}}</ref>||6.99 ± 2.43||2.30
|-
|[[File:1-methylcocaine.svg|x120px]] || (—)-1-methyl-cocaine|| Me ||163 ± 23||435 ± 77||488 ± 101||"unappreciable"||1.13 μM||16.01 ± 1.90||2.67
|-
|[[File:1-ethylcocaine.svg|x120px]] || (—)-1-ethyl-cocaine|| Et ||95.1 ± 17.0<sup>'''ɑ'''</sup>||1,106 ± 112||598 ± 179||—||—||—||3.20
|-
|[[File:1-propylcocaine.svg|x150px]] || (—)-1-n-propyl-cocaine||''n''-Pr ||871 ± 205<sup>'''ɑ'''</sup>||2,949 ± 462<sup>'''b'''</sup>||796 ± 195||—||—||—||3.56
|-
|[[File:1-pentylcocaine.svg|x160px]] || (—)-1-n-pentyl-cocaine||''n''-C<sub>5</sub>H<sub>11</sub> ||1,272 ± 199<sup>'''b'''</sup>||1,866 ± 400<sup>'''ɑ'''</sup>||1,596 ± 21<sup>'''b'''</sup>||—||—||—||4.64
|-
|[[File:1-phenylcocaine.svg|x150px]] || (—)-1-phenyl-cocaine|| Ph ||32.3 ± 5.7<sup>'''b'''</sup>||974 ± 308||1,980 ± 99<sup>'''b'''</sup>||524 ''nM''||198 ''nM''||0.29 ± 0.07||3.77
|}
*<small><sup>'''ɑ'''</sup>, ''P'' < 0.05 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)</small>
*<small><sup>'''b'''</sup>, ''P'' < 0.01 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)</small>
*<small><sup>'''c'''</sup>Lidocaine was found to have a value of 39.6 ± 2.4, the weakest of all tested.</small>
*<small><sup>'''d'''</sup>Same reference gives 25.9 ± 2.4 μM for (+)-cocaine and 13.6 ± 1.3 μM for norcocaine. Comparably it gives 12.7 ± 1.5 μM for the sigmaergic affinity of (+)-amphetamine. Another reference gives 1.7-6.7 μM for (—)-cocaine. All values ''K''<sub>i</sub>.</small><ref>[http://www.nature.com/npp/journal/v26/n4/full/1395834a.html Involvement of the Sigma<sub>1</sub> Receptor in Cocaine-induced Conditioned Place Preference: Possible Dependence on Dopamine Uptake Blockade] Pascal Romieu et al. Neuropsychopharmacology (2002) 26 444-455.10.1038/S0893-133X(01)00391-8</ref>
*<small>'''Using same data-set as above table, the following compounds were found to compare as:'''</small>
**<small>CFT @ DAT = 39.2 ± 7.1 (n = 5)</small>
**<small>fluoxetine @ SERT = 27.3 ± 9.2 (n = 3)</small>
**<small>desipramine @ NET = 2.74 ± 0.59 (n = 3)</small>
Cocaine analogs substituting the C1-tropane ring position, requiring sulfinimine (''N''-sulfinyl-imine) chemistry (before the innovation of which were untenable) which bind unlike the typical configuration at DAT (open to out) as cocaine (with its terminal D79-Y156 distance of 6.03 Å), or in the atypical (closed to out) conformation of the benztropines (3.29 Å). Though closer to the open to out: (—)-1-methyl-cocaine = 4.40 Å & (—)-1-phenyl-cocaine = 4.89 Å, and exhibiting preferential interaction with outward facing DAT conformation, they appear to have the lack of behavioral stimulation as-like the closed to out type. Despite having non-stimulant behavior profiles, they still seem to have anti-depressant behavioral profiles.<ref name="ReithAli2012"/>

The C1 phenyl analog is ten times stronger than cocaine as a dopamine reuptake pump ligand, and twenty four times stronger as a local anesthetic (voltage-dependent Na+ channel blocker), whereas the C1 methyl analog is 2.3 times less potent as a local anesthetic.<ref name="ReithAli2012"/>

''cf.'' [[Chemistry:List of cocaine analogues#See also|hydroxytropacocaine]] for a natural alkaloid (lacking however, the 2-position carbmethoxy) that is a C1 substituent with a [[Chemistry:Hydroxy group|hydroxy group]].

===2''β''-substitutions===

{| class="wikitable sortable"
|+Direct 2''β'' Substitutions{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973 (49th page of article)] §C. & Page #974 (50th page of article) Figure 31 & Page #976 (52nd page of article) Table 29.}}<br><sup>(IC<sub>50</sub> nM values)</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''R''
! DAT
[<sup>3</sup>H]WIN 35428
! 5-HTT
[<sup>3</sup>H]Paroxetine
! NET
[<sup>3</sup>H]Nisoxetine
! Selectivity
5-HTT/DAT
! Selectivity
NET/DAT
|-
|rowspan=17|[[File:Cocaine analog 196a-o.svg|200px|Satendra Singh Rev]]
|-
| (Cocaine) || [[Chemistry:Methyl group|Me]] ||89 ± 4.8||1045 ± 89||3298 ± 293||11.7||37.0
|-
| 196a<br>([[Chemistry:Cocaethylene|Cocaethylene]]) || [[Chemistry:Ethyl group|Et]] ||195 ± 45||5801 ± 493||10000 ± 751||29.7||51.3
|-
| 196b || ''n''-Pr ||196 ± 46||4517 ± 430||6124 ± 262||23.3||31.2
|-
| 196c || ''i''-Pr ||219 ± 48||25224 ± 1498||30384 ± 1685||115||139
|-
| 196d || Ph ||112 ± 31||33666 ± 3330||31024 ± 1909||300||277
|-
| 196e || Bn||257 ± 14||302 ± 23||20794 ± 950||1.2||80.9
|-
| 196f || β-phenethyl ||181 ± 10||615 ± 52||19944 ± 1026||3.4||110
|-
| 196g || γ-phenylpropyl ||147 ± 19||374 ± 15||4893 ± 344||2.5||33.3
|-
| 196h || [[Chemistry:Cinnamic acid|cinnamyl]] ||371 ± 15||368 ± 6.3||68931 ± 3476||1.0||186
|-
| 196i || ''p''-NO<sub>2</sub>-β-phenethyl ||601 ± 28|| - || - || - || -
|-
| 196j || ''p''-Cl-β-phenethyl ||271 ± 12|| - || - || - || -
|-
| 196k || ''p''-NH<sub>2</sub>-β-phenethyl ||72 ± 7|| - || - || - || -
|-
| 196l || ''p''-[[Chemistry:Isothiocyanate|NCS]]-β-phenethyl||196 ± 14|| - || - || - || -
|-
| 196m || ''p''-[[Chemistry:Azide|azido]]-β-phenethyl ||227 ± 19|| - || - || - || -
|-
| 196n || (''p''-NHCOCH<sub>2</sub>Br)β-phenethyl ||61 ± 6|| - || - || - || -
|-
| 196o || (''p''-NHCO(CH<sub>2</sub>)<sub>2</sub>CO<sub>2</sub>Et)β-phenethyl ||86 ± 4|| - || - || - || -
|-
|rowspan=5|[[File:Cocaine analog 197a-d.svg|200px|Satendra Singh Rev]]|| 197a || NH<sub>2</sub> ||753 ± 41.3||13725 ± 1256||3981 ± 229||18.2||5.3
|-
| 197b || -NMe<sub>2</sub> ||127 ± 6.36||143713 ± 8854||7329 ± 158||1131||57.7
|-
| 197c || -N(OMe)Me ||60 ± 6.4||28162 ± 2565||3935 ± 266||469||65.6
|-
| 197d || -NHMe ||2424 ± 118||44798 ± 2105||4213 ± 206||18.5||1.7
|-
| 197e<br>([[Chemistry:Benzoylecgonine|Benzoylecgonine]]) || -OH || 195000 || - || - || - || -
|-
|rowspan=2|[[File:Cocaine analog 196-197.svg|200px|Satendra Singh Rev]]|| 197f || HOCH<sub>2</sub>- ||561 ± 149|| - || - || - || -
|-
| 197g<br>([[Chemistry:Tropacocaine|Tropacocaine]]) || H ||5180 ± 1160|| - || - || - || -
|}

{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 2''β''-Substituted Analogue Structures
|-
! 196a ([[Chemistry:Cocaethylene|Cocaethylene]]) !! 196b !! 196c !! 196d !! 196e
|-
| [[File:Cocaine analog 196a.svg|x145px]] || x145px || x145px || x145px || [[File:Cocaine analog 196e.svg|x145px]] 
|-
! 196f !! 196g !! 196h !! 196i !! 196j 
|-
| [[File:Cocaine analog 196f.svg|x165px]] || x165px || x165px || x165px || [[File:Cocaine analog 196j.svg|x165px]] 
|-
! 196k !! 196l !! 196m !! 196n !! 196o
|-
| [[File:Cocaine analog 196k.svg|x165px]] || x165px || x165px || x165px || [[File:Cocaine analog 196o.svg|x165px]] 
|-
! 197a !! 197b !! 197c !! 197d !! 197e 
|-
| [[File:Cocaine analog 197a.svg|x145px]] || x145px || x145px || x145px || [[File:Cocaine analog 197e.svg|x145px]] 
|-
! 197f !! 197g 
|-
| [[File:Cocaine analog 197f.svg|x145px]] || [[File:Cocaine analog 197g.svg|x145px]] 
|-
|}

Compounds '''196e-h''' possess greater SERT affinity than cocaine, but possess weaker NET/DAT affinities (with the exception of '''196g''' at NET). Compounds '''196k''', '''196n''', '''196o''', and '''197c''' all possess greater DAT affinity than cocaine. Compound '''197b''' (dimethyl amide) displayed a 1,131-fold increased selectivity in affinity over the serotonin transporter, with only slight reductions in potency for the dopamine & norepinephrine transporters.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Final ¶ (5th), Second line.}} Whereas '''197c''' (Weinreb amide, N-methoxy-N-methyl amide) had a 469× increase at [[Biology:Serotonin transporter|SERT]], with greater affinity for [[Biology:Dopamine transporter|DAT]] than cocaine and an equal [[Biology:Norepinephrine transporter|NET]] affinity.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#51 Page #975 (51st page of article)] First ¶, first line.}} '''197b''' was 137×, and '''196c''' 27× less potent at binding to the serotonin transporter, but both had a NET / DAT ratio that made for a better [[Chemistry:Dopaminergic|dopaminergic]] than cocaine.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#51 Page #975 (51st page of article)] First ¶, 4th line.}} The consideration that large, bulky C2 substituents would alter the spatial conformation of the tropane ring system by distorting the piperidine portion of the system and thus hamper binding{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50st page of article)] First (left) column, third ¶}} appears to be unfounded.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #937 (13th page of article)] Second (right) column, first ¶. Above/before §2}} 

[[Chemistry:Benzoylecgonine|Benzoylecgonine]] ('''197e''') is the inactive primary metabolite of cocaine generated through hydrolysis of the C2 methyl ester. ''In vitro'' binding studies indicate that benzoylecgonine is ~2,200x less potent than cocaine at the dopamine transporter, possibly due to [[Physics:Zwitterion|zwitterion]] [[Physics:Ion#Formation|formation]] preventing strong DAT binding. In contrast to ''in vitro'' studies, the lack of activity observed in ''in vivo'' studies is likely the result of reduced [[Biology:Blood–brain barrier|blood–brain barrier]] penetration than formation of a [[Physics:Zwitterion|zwitterion]].{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50st page of article)] First (left) column, fourth ¶}}

====[[Chemistry:Bioisostere|Bioisostere]] 2-position carbmethoxy-ester functional replacements====
{| class="wikitable sortable"
|+2''β''-isoxazole and isoxazoline ring containing analogues{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}}{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}}{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}}<br><sup>IC<sub>50</sub> nM values</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''R''
! [<sup>3</sup>H][[Chemistry:Mazindol|Mazindol]]
! [<sup>3</sup>H]DA
! Selectivity
Uptake/Binding
|-
| || (Cocaine) || (H) ||580 ± 70||570 ± 180||1.0
|-
|rowspan=6|[[File:Cocaine analog 198.svg|200px|Satendra Singh Rev]]
|-
| 198a || H ||520 ± 40||260 ± 70||0.5
|-
| 198b || CO<sub>2</sub>Et (5′-carboethoxy-)||120 ± 10||290 ± 40||2.4
|-
| 198c || [[Chemistry:Tert-Butyloxycarbonyl protecting group|BOC]] ||2230 ± 220||1820 ± 810||0.8
|-
| 198d || Ph ||2000 ± 640||2920 ± 1620||1.5
|-
| 198e || CH=CHCO<sub>2</sub>Me ||3600 ± 400||3590 ± 1180||1.0
|-
|rowspan=3|[[File:Singh 199a-b.svg|x140px]]
|-
| 199a || β(or ''R'')CO<sub>2</sub>Et ||710 ± 150||1060 ± 340||1.5
|-
| 199b || α(or ''S'')CO<sub>2</sub>Et ||5830 ± 630||8460 ± 620||1.4
|-
| [[File:Singh 200.svg|x140px]] || 200 || ||880 ± 350||400 ± 140||0.4
|}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 2''β''-isoxazole and isoxazoline ring containing analogues
|-
! 198a !! 198b !! 198c !! 198d 
|-
| [[File:Cocaine analog 198a.svg|x165px]] || x165px || x165px || [[File:Cocaine analog 198d.svg|x165px]] 
|-
! 198e !! 199a !! 199b !! 200
|-
| [[File:Cocaine analog 198e.svg|x165px]] || x165px || x165px ||[[File:Singh 200.svg|x140px]]
|}

====Vinylogous 2''β''-position carbmethoxy-ester functional replacements====

{| class="wikitable sortable"
|+vinylogous 2''β'' analogues{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}}<br><sup>Data-set congruent to, and aggregate with, preceding table<br>IC<sub>50</sub> nM values</sup>
! Structure
! S. Singh's<br>alphanumeric<br>assignation
! ''R''
! [<sup>3</sup>H]Mazindol
! [<sup>3</sup>H]DA
! Selectivity
Uptake/Binding
|-
|rowspan=7|[[File:Cocaine analog 201.svg|220px]]
|-
| Cocaine || || 580 ± 70|| 570 ± 180 || 1
|-
| 201a || H ||1730 ± 550||1120 ± 390||0.6
|-
| 201b || Cl ||222 ± 49||368 ± 190||1.6
|-
| 201c || CO<sub>2</sub>Et ||50 ± 10||130 ± 10||2.6
|-
| 201d || CH=CHCO<sub>2</sub>Et ||1220 ± 100||870 ± 50||0.7
|-
| 201e || PO(OEt)<sub>2</sub> ||4850 ± 470||5500 ± 70||1.1
|}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Vinylogous 2''β'' analogues
|-
! 201a !! 201b !! 201c !! 201d !! 201e
|-
| [[File:Cocaine analog 201a.svg|x150px]] || x150px || x150px || x150px || [[File:Cocaine analog 201e.svg|x150px]]
|}
Compounds '''201b''' & '''201c''' were significantly more potent than cocaine while compounds '''201a''', '''201d''' & '''201e''' were significantly less potent. This finding indicates that the presence of a hydrogen bond acceptor (''i.e.'' carbomethoxy) at the 2''β'' position is not absolutely necessary for the creation of high affinity cocaine analogues.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#52 Page #976 (52nd page of article)]}}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Miscellaneous 2''β''-substituted cocaine analogues 
|-
! [<sup>2</sup>H<sub>5</sub>-phenyl]-cocaine !! HPBE !! [''<sup>2</sup>H<sub>3</sub>-N-methyl'']-cocaine !! C2-ethyl-OSO<sub>2</sub>CF<sub>2</sub><br>cocaine !! 2-[(2-methoxy-2-oxoethoxy)methyl]<br>cocaine
|-
|-
|}

===''N''-modifications===

{| class="wikitable sortable"
|+Nitrogen Substitutions<br>Mazindol comparison table<br>(<sup>'''ɑ'''</sup>''β''-CFT comparison notation){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#54 Page #978 (54th page of article)] §D & Page #980 (56th page of article) Figure 33 & Page #981 (57th page of article) Table 32.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''N''8-''R''
! [<sup>3</sup>H]Mazindol<br>binding
! [<sup>3</sup>H]DA<br>uptake
! Selectivity
Uptake/Binding
|-
| [[File:Cocaine methiodide.svg|240px]] ||217<br>(Cocaine methiodide)||-||10700 ± 1530<sup>'''ɑ'''</sup>|| - || -
|-
|rowspan=17|[[File:Cocaine analog 219.svg|210px|Satendra Singh Rev]]|| (Cocaine) || CH<sub>3</sub> ||280 ± 60<br>102<sup>'''ɑ'''</sup>||320 ± 10||1.1
|-
| 218<br>([[Chemistry:Norcocaine|Norcocaine]]) || H ||303 ± 59<sup>'''ɑ'''</sup>|| - || -
|-
| 219a || Bn ||668 ± 67<sup>'''ɑ'''</sup>|| - || -
|-
| 219b || Ac ||3370 ± 1080<sup>'''ɑ'''</sup>|| - || -
|-
| 219c || CH<sub>2</sub>CH<sub>2</sub>OH ||700 ± 100||1600 ± 200||2.3
|-
| 219d || CH<sub>2</sub>CO<sub>2</sub>CH<sub>3</sub> ||480 ± 40||1600 ± 100||3.3
|-
| 219e || CH<sub>2</sub>CO<sub>2</sub>H ||380 ± 20||2100 ± 400||5.5
|-
| 220a || SO<sub>2</sub>CH<sub>3</sub> ([[Chemistry:Mesyl|Ms]]) ||1290 ± 80||1970 ± 70||1.5
|-
| 220b || SO<sub>2</sub>CF<sub>3</sub> (Tf) ||330 ± 30||760 ± 20||2.3
|-
| 220c || SO<sub>2</sub>NCO ||120 ± 10||160 ± 10||1.3
|-
| 220d || SO<sub>2</sub>Ph ||20800 ± 3500|| 61000 ||2.9
|-
| 220e || SO<sub>2</sub>C<sub>6</sub>H<sub>4</sub>-4-NO<sub>2</sub> (nosyl) ||5720 ± 1140||18800 ± 90||3.3
|-
| 220f || SO<sub>2</sub>C<sub>6</sub>H<sub>4</sub>-4-OCH<sub>3</sub> ||6820 ± 580||16400 ± 1400||2.4
|-
| 221a || NO ||99500 ± 12300||231700 ± 39500||2.3
|-
| 221b || NO<sub>2</sub> ||7500 ± 900||21200 ± 600||2.8
|-
| 221c || NHCOCH<sub>3</sub> || >1000000 || >1000000 || -
|-
| 221d || NH<sub>2</sub> || - || - || -
|}
*<sup>'''ɑ'''</sup><small>IC<sub>50</sub> (nM) for displacement of [<sup>3</sup>H]WIN 35428</small>

{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | N-Modified Analogue Structures
|-
! [[Chemistry:Norcocaine|Norcocaine]] (218) !! 219a !! 219b !! 219c
|-
| [[File:Cocaine analog 218 (norcocaine).svg|x140px]] || x140px || x140px || [[File:Cocaine analog 219c.svg|x140px]]
|-
! 219d !! 219e !! 220a !! 220b
|-
| [[File:Cocaine analog 219d.svg|x140px]] || x140px || x140px || [[File:Cocaine analog 220b.svg|x140px]]
|-
! 220c !! 220d !! 220e !! 220f
|-
| [[File:Cocaine analog 220c.svg|x140px]] || x140px || x140px || [[File:Cocaine analog 220f.svg|x140px]]
|-
! 221a !! 221b !! 221c !! 221d
|-
| [[File:Cocaine analog 221a.svg|x140px]] || x140px || x140px || [[File:Cocaine analog 221d.svg|x140px]]
|}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Miscellaneous ''N''-modified cocaine analogues
|-
! ''N''6 Regioisomer<ref name="Carroll">{{US patent|6479509}}</ref> !! ''N''7 Regioisomer<ref name="Carroll"/> !! ''ortho''-Phenyl ''N''7 Regioisomer<ref name="Carroll"/> !! 8-Oxa cocaine<ref>{{Cite journal | doi = 10.1016/S0960-894X(99)00273-5| pmid = 10406650| title = Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity| journal = Bioorganic & Medicinal Chemistry Letters| volume = 9| issue = 13| pages = 1831–1836| year = 1999| last1 = Kozikowski | first1 = A. P. | last2 = Simoni | first2 = D. | last3 = Roberti | first3 = M. | last4 = Rondanin | first4 = R. | last5 = Wang | first5 = S. | last6 = Du | first6 = P. | last7 = Johnson | first7 = K. M. | doi-access = free }}</ref><br><small>(cf Meltzer with PTs)</small>
|-
| [[File:(1R,3S,5S)-6-methyl-6-azabicyclo(3.2.1)octan-3-yl_benzoate.svg|x140px]] || x140px || x140px || [[File:8-Oxa Cocaine Structure.svg|x140px]]
|}

=== Tricyclic cocaine analogues ===
====8 to 2 tethered analogues====
{| class="wikitable"
|+Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes ''K<sub>i</sub>'' (nM) {{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#39 Page #964 (39th page of article)] Table 23.}}
!Compound<br />(''S. Singh's #'') 
!Structure
![<sup>3</sup>H]Mazindol binding
![<sup>3</sup>H]DA uptake
![<sup>3</sup>H]5-HT uptake
![<sup>3</sup>H]NE uptake
!selectivity<br />[<sup>3</sup>H]5-HT/[<sup>3</sup>H]DA
|-
|cocaine||  ||375 ± 68||423 ± 147||155 ± 40||83.3 ± 1.5||0.4
|-
|''(–)-128''||  ||54.3 ± 10.2||60.3 ± 0.4||1.76 ± 0.23||5.24 ± 0.07||0.03
|-
|''(+)-128''||  ||79 ± 19||114 ± 28||1.48 ± 0.07||4.62 ± 0.31||0.01
|-
|''(±)-128''|| [[File:Singh 128.svg|x140px]] ||61.7 ± 8.5||60.3 ± 0.4||2.32 ± 0.23||2.69 ± 0.12||0.04
|-
|''129''|| [[File:Singh 129.svg|x140px]] ||6.86 ± 0.43||24.0 ± 1.3||1.77 ± 0.04||1.06 ± 0.03||0.07
|-
|''130a''|| [[File:Singh 130a.svg|x140px]] ||17.2 ± 1.13||10.2 ± 1.4||78.9 ± 0.9||15.0 ± 0.4||7.8
|-
|''131a''|| [[File:Singh 131a.svg|x140px]] ||4.00 ± 0.07||2.23 ± 0.12||14.0 ± 0.6||2.99 ± 0.17||6.3 
|-
|''131b''|| [[File:Singh 131b.svg|x110px]] ||3.61 ± 0.43||11.3 ± 1.1||25.7 ± 4.3||4.43 ± 0.01||2.3
|-
|''132a''|| [[File:Singh 132a.svg|x160px]] ||13.7 ± 0.8||14.2 ± 0.1||618 ± 87||3.84 ± 0.35||43.5 
|-
|''133a''|| [[File:Singh 133a.svg|x140px]] ||149 ± 6||149 ± 2||810 ± 80||51.7 ± 12||5.4
|-
|}
''See ''N''-front & back bridged phenyltropanes.''
{| class="wikitable"
|+Derivations upon fusions of the tropane's nitrogen bridge{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#56 Page #980 (56th page of article)] Scheme 52.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation
! [<sup>3</sup>H]Mazindol
! [<sup>3</sup>H]DA
! Selectivity
Uptake/Binding
|-
| [[File:Cocaine analog 222.svg|200px]] || 222 ||44900 ± 6200||115000 ± 15700||2.6
|}
Back-bridged cocaine analogues are considered more akin to untethered cocaine analogs & phenyltropane derivatives (where the nitrogen [[Physics:Orbital hybridisation|lone pair is not fixed or constrained]]) and better mimics their affinities. This is due to when the eighth carbon tropane position is freely rotatable and unbound it preferably occupies the ''axial'' position as defining its least energy & most unhindered state. In front-bridged analogs the nitrogen lone pairings rigid fixity makes it reside in an ''equatorial'' placing for the piperidine ring-part of the tropane nucleus, pointing to the two-carbon & three methylene unit bridgehead; giving the attested front-bridged cocaine analogues preference for SERT over DAT.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#39 Page #963 (39th page of article)] 2nd (right side) column, 2nd paragraph.}}

==== 8 to 3 tethered analogues ====
{| class="wikitable sortable"
|+ Thiophene tricyclic tropane analogues<ref>{{cite journal |last1=Zhang |first1=A |last2=Zhou |first2=G |last3=Rong |first3=SB |last4=Johnson |first4=KM |last5=Zhang |first5=M |last6=Kozikowski |first6=AP |title=Thiophene derivatives: a new series of potent norepinephrine and serotonin reuptake inhibitors. |journal=Bioorganic & Medicinal Chemistry Letters |date=8 April 2002 |volume=12 |issue=7 |pages=993–5 |doi=10.1016/s0960-894x(02)00103-8 |pmid=11909701}}</ref>
! Structure
! Compound 
! ''R''
! ''X''
! [<sup>3</sup>H]DA Uptake 
! [<sup>3</sup>H]5-HT Uptake 
! [<sup>3</sup>H]NE Uptake 
! 5-HT/DA Selectivity
! NE/DA Selectivity
|-
| || Cocaine || || || 259 ± 19.9 || 155 ± 0.4 || 108 ± 3.5 || 0.60 || 0.42
|-
|rowspan=12| [[File:Zhang thiophene tropane.svg|120px]]
|-
| 5a || H || CO<sub>2</sub>Me || 268 ± 16.6 || 2046 ± 42 || 26.4 ± 1.9 || 7.63 || 0.10
|-
| 5b || Me || CO<sub>2</sub>Me || 403 ± 20 || 179 ± 38 || 4.9 ± 0.2 || 0.44 || 0.01
|-
| 5c || I || CO<sub>2</sub>Me || 368 ± 1.6 || 29 ± 1.6 || 5 ± 1.3 || 0.08 || 0.01
|-
| 7 || H || CO<sub>2</sub>''i''Pr || 428 ± 45.7 || 1150 ± 1.6 || 52.3 ± 12.0 || 2.69 || 0.12
|-
| 8 || H || CH<sub>2</sub>OH || ~3000 || ~1000 || ~300 || ~0.33 || ~ 0.1
|-
| 9 || H || CH<sub>2</sub>OAc || 610 ± 53 || 1530 ± 150 || 283 ± 16 || 2.51 || 0.46
|-
| 10 || H || CH<sub>2</sub>OCOC(CH<sub>3</sub>)<sub>3</sub>|| 1020 ± 70 || 168 ± 53.5 || 1180 ± 130 || 0.16 || 1.16
|-
| 11 || H || CH<sub>2</sub>OCOPh || 1750 ± 140 || 1.53 ± 0.19 || 894 ± 126 || 0.0009 || 0.51
|-
| 12 || H || CH<sub>2</sub>OCO-2-naphthyl || 1678 ± 124 || 169 ± 16 || 1234 ± 166 || 0.10 || 0.74
|-
| 13 || H || CH<sub>2</sub>NHCOCH<sub>3</sub> || 6140 ± 50 || 13330 ± 3150 || 2430 ± 340 || 2.17 || 0.39
|-
| 14 || H || CH<sub>2</sub>NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub> || 2300 ± 380 || 2360 ± 30 || 1700 ± 60 || 1.03 || 0.74 
|}

{| class="wikitable sortable"
|+ Conformationally constrained tricyclic tropane analogues<ref>{{cite journal |last1=Zhang |first1=Ao |last2=Zhou |first2=Guochun |last3=Hoepping |first3=Alexander |last4=Mukhopadhyaya |first4=Jayanta |last5=Johnson |first5=Kenneth M. |last6=Zhang |first6=Mei |last7=Kozikowski |first7=Alan P. |title=Further Studies on Conformationally Constrained Tricyclic Tropane Analogues and Their Uptake Inhibition at Monoamine Transporter Sites: Synthesis of ( Z )-9-(Substituted arylmethylene)-7-azatricyclo[4.3.1.0 3,7 ]decanes as a Novel Class of Serotonin Transporter Inhibitors |journal=Journal of Medicinal Chemistry |date=April 2002 |volume=45 |issue=9 |pages=1930–1941 |doi=10.1021/jm0105373|pmid=11960503 }}</ref>
! Structure
! Compound 
! ''R''
! ''X''
! [<sup>3</sup>H]DA Uptake 
! [<sup>3</sup>H]5-HT Uptake 
! [<sup>3</sup>H]NE Uptake 
! DA/5-HT Selectivity
! NE/DA Selectivity
|-
| || Cocaine || || || 423 ± 147 || 155 ± 0.4 || 108 ± 3.5 || 2.7 || 0.26
|-
|rowspan=20| [[File:Zhang tricyclic tropane.svg|120px]]
|-
| 8a || 4-F || CO<sub>2</sub>Me || 6620 ± 460 || 335 ± 45 || 584 ± 163 || 2.7 || 0.26
|-
| 8b || 4-Cl || CO<sub>2</sub>Me || 853 ± 58 || 34.3 ± 2.9 || 208 ± 111 || 24.8 || 0.24
|-
| 8c || 3-Cl || CO<sub>2</sub>Me || 7780 ± 1580 || 53.6 ± 17.2 || 231 ± 44 || 145 || 0.03
|-
| 8d || 4-Br || CO<sub>2</sub>Me ||495 ± 13 || 11 ± 3 || 178 ± 9 || 45 || 0.36
|-
| 8e || 4-I || CO<sub>2</sub>Me || 764 ± 11 || 21.9 ± 0.3 || 213 ± 31 || 34.9 || 0.28
|-
| 8f || 4-CF<sub>3</sub> || CO<sub>2</sub>Me || N/T || 12.6 ± 0.5 || 1830 ± 211 || N/T || N/T
|-
| 8g || H || CO<sub>2</sub>Me|| 481 ± 11 || 1140 ± 70 || 53 ± 16 || 0.42 || 0.11
|-
| 8h || 4-Me || CO<sub>2</sub>Me || 649 ± 2 || 15 ± 0.4 || 146 ± 28 || 43.3 || 0.22
|-
| 8i || 4-OCH<sub>3</sub> || CO<sub>2</sub>Me || 3130 ± 160 || 56 ± 4 || 187 ± 5 || 55.9 || 0.06
|-
| 8j || 4-''i''Pr || CO<sub>2</sub>Me || N/T || 10.2 ± 0.4 || 1110 ± 200 || N/T || N/T
|-
| 8k || 3,4-Cl<sub>2</sub> || CO<sub>2</sub>Me || 1920 ± 260 || 20 ± 1 || 1000 ± 280 || 96 || 0.52
|-
| 8l || 2,3-Cl<sub>2</sub> || CO<sub>2</sub>Me || 950 ± 107 || 354 ± 188 || 1210 ± 358 || 2.4 || 1.42
|-
| 8m || 3,5-Cl<sub>2</sub> || CO<sub>2</sub>Me || 5600 ± 400 || 437 ± 0.3 || 4100 ± 500 || 12.8 || 0.73
|-
| 8n || 3,4-F<sub>2</sub> || CO<sub>2</sub>Me || 7440 ± 19 || 101 ± 8.7 || 394 ± 98 || 73.7 || 0.05
|-
| 8o || 4-Br-3-Cl || CO<sub>2</sub>Me || 5420 ± 940 || 2.3 ± 0.1 || 459 ± 80 || 2360 || 0.08
|-
| 8p || 3-Cl-4-I || CO<sub>2</sub>Me || 3140 ± 450 || 1.8 ± 0.3 || 272 ± 55 || 1740 || 0.09
|-
| 8q || 2-Cl-4-I || CO<sub>2</sub>Me || 6640 ± 2080 || 74 ± 12.2 || 508 ± 21 || 89.7 || 0.08 
|-
| 8r || 3-Cl-4-Me || CO<sub>2</sub>Me || >10000 || 6.4 ± 1.3 || 198 ± 10 || >1560 || <0.02
|-
| 8s || 3,4-Me<sub>2</sub> || CO<sub>2</sub>Me || N/T || 10.1 ± 1.1 || 659 ± 128 || N/T || N/T
|-
|rowspan=5| [[File:Zhang tricyclic tropane 2.svg|120px]]
|-
| 8t || 1-Naphthyl || CO<sub>2</sub>Me || 9720 ± 700 || 121 ± 3 || 5370 ± 580 || 80.3 || 0.55
|-
| 8u || 2-Naphthyl || CO<sub>2</sub>Me || 735 ± 235 || 21 ± 9.9 || 157 ± 13 || 35 || 0.21
|-
| 8v || 1-Pyrenyl || CO<sub>2</sub>Me || 9920 ± 906 || 860 ± 20.6 || N/T || 11.5 || N/T
|-
| 8w || 9-Phenanthryl || CO<sub>2</sub>Me || 1640 ± 30 || 233 ± 44 || 13000 ± 1300 || 39.2 || 0.86
|}
*<small>"'''N/T'''" = "not tested"</small>

===Tropane ring contraction (azabornane) analogues===
[[File:NorbornaneBMEanalog.png|thumb|x150px|right|Comparison of tropane ring versus the norbornane in overlay emphasizing the conformational differences of the benzoyl branch between the tropane ring system (dark blue on right) and norbornane ring sustem (light blue on right).]]
{| class="wikitable sortable"
|+7-Azabicyclo[2.2.1]heptane Derivatives{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#43 Page #967 (43rd page of article)] §C. & Page #967 (43rd page of article) Table 25 }}
! Structure
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! DAT<br>[<sup>3</sup>H]WIN 35428<br>K<sub>i</sub> (nM) 
|-
| || (Cocaine) ||89 ± 4.8
|-
| [[File:Cocaine analogue 155a.svg|x140px]] || 155a || 60400 ± 4800
|-
| [[File:Cocaine analogue 155b.svg|x140px]] || 155b || 96500 ± 42
|-
| [[File:Cocaine analogue 155c.svg|x140px]] || 155c || 5620 ± 390
|-
| [[File:Cocaine analogue 155d.svg|x140px]] || 155d || 18900 ± 1700
|-
|}

===6/7 tropane position methoxycocaine & methoxypseudococaine analogues===
[[File:Methyl (1R,4R,5S)-4-chloro-8-methyl-3-(phenylsulfanyl)-8-azabicyclo(3.2.1)oct-2-ene-2-carboxylate.svg|thumb|right|Phenylsulfanyl, C2-C3 unsaturated nonisomeric (C2 inclusive) C4 chloro analog.<ref name="Carroll"/>]]
{| class="wikitable sortable"
|+Substitutions upon the 6 & 7 positions of the tropane{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)] §G & Page #983 (59th page of article) Figure 36 & Page #984 (60th page of article) Table 35.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''X''
! K<sub>i</sub> (nM)<br>[<sup>3</sup>H]Mazindol binding
! K<sub>i</sub> (nM)<br>[<sup>3</sup>H]DA uptake
! Selectivity
Uptake/Binding
|-
| || (Cocaine) || ||280 ± 60||320 ± 10||1.1
|-
| || (Pseudococaine) || ||10400 ± 300||13800 ± 1500||1.3
|-
| [[File:Cocaine analog 225a.svg|220px]] || 225a || 2β, 6β-OCH<sub>3</sub> ||98000 ± 12000||68000 ± 5000||0.7
|-
| [[File:Cocaine analog 225b.svg|220px]] || 225b || 2α, 6β-OCH<sub>3</sub> ||190000 ± 11000||510000 ± 110000||2.7
|-
| [[File:Cocaine analog 225c.svg|220px]] || 225c || 2β, 7β-OCH<sub>3</sub> ||4200 ± 100||6100 ± 200||1.4
|-
| [[File:Cocaine analog 225d.svg|220px]] || 225d || 2α, 7β-OCH<sub>3</sub> ||45000 ± 5000||110000 ± 4000||2.4
|-
| [[File:Cocaine analog 225e.svg|220px]] || 225e || 2α, 7α-OCH<sub>3</sub> ||54000 ± 3000||200000 ± 70000||3.7
|}

===3''β''-position 2′—(6′) & 2''β''-substitution combination analogues===

{| class="wikitable sortable"
|+4′-Iodococaine-2''β''-substituted analogues{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#55 Page #979 (55th page of article)] Table 31.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation
! 2''β''-''R''
! C2′-''R''
! IC<sub>50</sub> (nM)<br>(displacement of [<sup>3</sup>H]WIN 35428)
|-
|rowspan=11|[[File:Cocaine_analog_211.svg|220px]]
|-
| 211a || CO<sub>2</sub>OH || H ||6214 ± 1269
|-
| 211b || CH<sub>2</sub>OCOCH<sub>3</sub> || H ||2995 ± 223
|-
| 211c || CONHCH<sub>3</sub> || H || >100000
|-
| 211d || CO<sub>2</sub>Et || H ||2031 ± 190
|-
| 211e || CO<sub>2</sub>-''i''-Pr || H ||1377 ± 10
|-
| 211f || CO<sub>2</sub>Ph || H ||2019 ± 253
|-
| 211g || CO<sub>2</sub>CH<sub>2</sub>Ph || H ||4602 ± 325
|-
| 211h || 3-phenyl-1,2,4-oxadiazole || H ||3459 ± 60
|-
| 211i || CH=CH<sub>2</sub> || H ||2165 ± 253
|-
| 211j || CH<sub>2</sub>CH<sub>3</sub> || H ||2692 ± 486
|-
| [[File:Cocaine analog 212.svg|200px]] || 212 || CO<sub>2</sub>-''i''-Pr || HO ||663 ± 70<br>4507 ± 13<sup>'''ɑ'''</sup><br>34838 ± 796<sup>'''b'''</sup>
|}

*<sup>'''ɑ'''</sup><small>For displacement of [<sup>3</sup>H]paroxetine (5-HTT & NET)</small>
*<sup>'''b'''</sup><small>For displacement of [<sup>3</sup>H]nisoxetine (5-HTT & NET)</small>

{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 4′-Iodococaine-2''β''-substituted analogues
|-
! 211a !! 211b !! 211c !! 211d !! 211e
|-
| [[File:Cocaine analog 211a.svg|200px]] || 200px || 200px || 200px || [[File:Cocaine analog 211e.svg|200px]]
|-
! 211f !! 211g !! 211h !! 211i !! 211j
|-
| [[File:Cocaine analog 211f.svg|200px]] || 200px || 200px || 200px || [[File:Cocaine analog 211j.svg|200px]]
|}

===3''β''-Carbamoyl analogues===

{| class="wikitable sortable"
|+3-position carbamoyl linkage substituting benzoyloxy analogues{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#57 Page #981 (57th page of article)] §E & Page #982 (58th page of article) Table 33.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''X''
! IC<sub>50</sub> (nM)<br>inhibition of [<sup>3</sup>H]Cocaine binding<br>(Rat Striatal Tissue)
! IC<sub>50</sub> (nM)<br>inhibition of [<sup>3</sup>H]DA uptake<br>(Rat Striatal Tissue)
! Selectivity<br>uptake/binding
|-
| || (Cocaine) || (H) ||70 ± 10||210 ± 70||3.0
|-
|rowspan=6|[[File:Cocaine analog 223a-e.svg|x120px]]
|-
| 223a || H ||5600 ± 700||52600 ± 3000||9.4
|-
| 223b || 4-NO<sub>2</sub> ||1090 ± 250||5700 ± 1200||5.2
|-
| 223c || 4-NH<sub>2</sub> ||63300 ± 12200|| >100000 || -
|-
| 223d || 4-N<sub>3</sub> ||1000 ± 240||1180 ± 360||1.2
|-
| 223e || 4-NCS ||260 ± 60||490 ± 80||1.9
|-
|rowspan=5|[[File:Cocaine analog 223f-i.svg|x120px]]
|-
| 223f || 3-NO<sub>2</sub> ||37 ± 10||178 ± 23||4.8
|-
| 223g || 3-NH<sub>2</sub> ||2070 ± 340||23100 ± 900||11.1
|-
| 223h || 3-N<sub>3</sub> ||630 ± 150||3900 ± 1590||6.2
|-
| 223i || 3-NCS ||960 ± 210||4900 ± 420||5.1
|}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 3''β''-Carbamoyl analogues
|-
! 223a !! 223b !! 223c
|-
| [[File:Cocaine analog 223a.svg|x160px]] || x160px || [[File:Cocaine analog 223c.svg|x160px]]
|-
! 223d !! 223e !! 223f
|-
| [[File:Cocaine analog 223d.svg|x160px]] || x160px || [[File:Cocaine analog 223f.svg|x160px]]
|-
! 223g !! 223h !! 223i
|-
| [[File:Cocaine analog 223g.svg|x160px]] || x160px || [[File:Cocaine analog 223i.svg|x160px]]
|}

===Phenyl 3-position linkage substitutions===
<div style="background-color: #CFCFCF; border:10px solid #666666">
[[File:Phenyltropane.gif|thumb|A 3-Dimensional ([[Physics:Ball-and-stick model|stick-&-ball]]) rendering of Troparil: A structural analogue of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands; those of the phenyltropane class. (Here it is depicted in an unfavourable conformation of the O-Me; The methyl has to be at the other oxygen and ''[[Cis–trans isomerism|trans]]'' to optimize its functional stimulation.)]]
{{multiple image
 | align = left
 | direction = vertical
 | footer = The top image above is a 2-Dimensional emulation of the orientation for the animated 3D image to the far right, with a methoxy that is distal from the phenyl group and ''cis''. While the alternate image below that to its bottom shown above is one with the carboxyl methyl group proximal to the phenyl, in its optimum conformation, with a likewise optimum ''trans'' configuration.
 | image1 = Troparil w ph distal cis OMe.png
 | width1 = 190
 | image2 = Troparil w ph proximal trans OMe.png
 | width2 = 200
 }}

See: List of phenyltropanes (Many phenyltropanes are derived from cocaine metabolites, such as [[Chemistry:Methylecgonidine|methylecgonidine]], as [[Biology:Precursor|precursors]]. Whereas fully synthetic methods have been devised from the starting material of vinylcarbenoids & pyrroles.)<ref>{{cite journal | pmid = 8420793 | volume=244 | issue=1 | title=Novel 2-substituted cocaine analogs: binding properties at dopamine transport sites in rat striatum | year=1993 | journal=Eur. J. Pharmacol. | pages=93–7 | last1 = Davies | first1 = HM | last2 = Saikali | first2 = E | last3 = Sexton | first3 = T | last4 = Childers | first4 = SR | doi=10.1016/0922-4106(93)90063-f}}</ref>

The difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the [[Centroid|centroid]] of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 [[Angstrom|Å]] for phenyltropanes and 7.7 [[Angstrom|Å]] for cocaine or analogs with the benzoyloxy intact.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#46 Page #970 (46th page of article)] §B, 10th line}} This may account for PTs increased behavioral stimulation profile over cocaine.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] 1st ¶, 10th line}} Differences in binding potency have also been explained considering solvation effects; cocaine containing 2''β'',3''β''-ester groups being calculated as more solvated than the WIN-type compounds (i.e. troparil). Higher p''K''<sub>ɑ</sub>s of the tropane nitrogen (8.65 for cocaine, 9.55 for troparil & 11.95 for vinyl analogue '''43a'''), decreased aqueous solvation & decreased conformational flexibility added to increased binding affinity.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#25 Page #949 (25th page of article)] 3rd ¶, 20th line}}

[[File:WIN 35,065-2.svg|x150px]]
[[File:WF-31.svg|x170px]]
[[File:RTI-11W.svg|x150px]]
[[File:WF-23.svg|x160px]]

Despite the observation of increased stimulation, phenyltropanes lack the local anesthetic sodium channel blocking effect that the benzoyloxy imparts to cocaine. Beside topical affect, this gives cocaine an affinity for binding to sites on the dopamine and serotonin sodium dependent transport areas that are distinct & specific to MAT in contrast to the general sodium channels; creating a separate mechanism of relational affinity to the transporters in addition to its inhibition of the reuptake for those transporters; this is unique to the local anesthetic value in cocaine & analogues with a similar substitute for the benzoyloxy that leaves the sodium channel blockage ability intact. Rendering such compounds as different functionally in their relation to MAT contrasted to phenyltropane analogues which have the local anesthetic bridge removed.<ref>{{cite web|url=http://www.drugbank.ca/drugs/DB00907 |title=Drugbank website "drug card", "(DB00907)" for Cocaine: Giving ten targets of the molecule in vivo, including dopamine/serotonin sodium channel affinity & K-opioid affinity |publisher=Drugbank.ca |accessdate=9 March 2010}}</ref> (Requiring some of the sodium ions to be pumped from the axon via Na+/K+-ATPase). In addition, it even has been postulated that a crucial role regarding the electron energy imparted via voltage sensitization (and thus [[Biology:Action potential|action potential]] blockage with a molecule capable of intersecting its specific channel, in the case of cocaine a [[Biology:Sodium channel|sodium channel]], that potentially serves in [[Physics:Elementary charge#Quantization|re-quantifying]] its charge) upon a receptor binding site may attenuate the mediating influence of the inhibitory regulation that autoreceptors play by their slowing neurotransmitter release when an [[Biology:Efflux (microbiology)|efflux]] is created through an instance of agonism by a compound; allowing said efflux to be continued without the body's attempt to maintain [[Homeostasis|homeostasis]] enacting in as readily responsive a manner to its conformational change.<ref>{{cite journal | last1 = Sahlholm | first1 = Kristoffer | last2 = Nilsson | first2 = Johanna | last3 = Marcellino | first3 = Daniel | last4 = Fuxe | first4 = Kjell | last5 = Århem | first5 = Peter | year = 2012 | title = Voltage sensitivities and deactivation kinetics of histamine H<sub>3</sub> and H<sub>4</sub> receptors | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1818 | issue = 12| pages = 3081–3089 | doi = 10.1016/j.bbamem.2012.07.027 | pmid = 22885137 | doi-access = free }} ''...Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors...''</ref>

{| class="wikitable"
|+ Various phenyltropane examples
|-
|
<div style="background-color: #FFFFFF; border:10px solid #E9E9E9">
[[File:RTI-353 structure.png|x180px]]
[[File:RTI-150.png|x200px]]
[[File:RTI-171 structure.png|x195px]]
[[File:RTI-336.png|x185px]]
<br>
[[File:Altropane.svg|x170px]]
[[File:Ioflupane.png|x190px]]
[[File:Brasofensine.svg|x200px]]
[[File:Tesofensine chemical structure.png|x140px]]
</div>
|}
{{clear}}
</div>

===3''β''-Alkylphenyltropane & 3''β''-Alkenyl analogues===

{| class="wikitable sortable"
|+3-position alkylphenyl linkage substituting benzoyloxy analogues{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)] §F, Table 34 & Figure 35.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''n''
! IC<sub>50</sub> (nM)<br>[<sup>3</sup>H]Cocaine binding
! IC<sub>50</sub> (nM)<br>[<sup>3</sup>H]DA uptake
! Selectivity<br>uptake/binding
|-
| || (Cocaine) || ||101 ± 26||209 ± 20||2.1
|-
|rowspan=4|[[File:Cocaine_analog_224.svg|x140px]]
|-
| 224a || <sub>1</sub> ||885 ± 18||1020 ± 52||1.1
|-
| 224b || <sub>2</sub> ||9.9 ± 0.33||70.5 ± 1.0||7.1
|-
| 224c || <sub>3</sub> ||344 ± 12||2680 ± 190||7.8
|-
| || 224d ||  ||71.6 ± 0.7||138 ± 9||1.9
|-
| || 224e ||  ||2.10 ± 0.04||5.88 ± 0.09||2.8
|}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 3''β''-Alkylphenyltropane & 3''β''-Alkenyl analogues
|-
! 224a !! 224b !! 224c !! 224d !! 224e 
|-
| [[File:Cocaine analog 224a.svg|x140px]] || x120px || x140px || | x140px || [[File:Cocaine analog 224e.svg|x120px]] 
|-
|}

The compound '''224e''', the 3''β''-styrene analogue, had the highest potency in its group. While '''224b''' & '''224c''' showed the most selectivity, with '''224b''' having a ten-fold greater potency for the dopamine transporter than cocaine.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)] 3rd ¶, lines 2, 5 & 6.}}

===6-Alkyl-3-benzyltropane analogues===

{| class="wikitable"
|+6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#60 Page #984 (60th page of article)] Figure 37.}}
! Sub-category<br>(''S. Singh compound #'')
! a<br>''R''=H
! b<br>''R''=Me
! c<br>''R''=Et
! d<br>''R''=''n''-Pr
! e<br>''R''=''n''-Bu
! f<br>''R''=Bn
|-
|rowspan=2|2β,6α-isomers:<br>'''''(229a—f)'''''
|-
| [[File:Cocaine analog 229a.svg|x120px]] || x120px || x120px || x120px || x120px || [[File:Cocaine analog 229f.svg|x120px]]
|-
|rowspan=2|2α,6α-isomers:<br>'''''(230a—f)'''''
|-
|[[File:Cocaine analog 230a.svg|x110px]] || x110px || x110px || x120px || x120px || [[File:Cocaine analog 230f.svg|x120px]]
|-
|rowspan=2|2β,6β-isomers:<br>'''''(231a—f)'''''
|-
| [[File:Cocaine analog 229a.svg|x110px]] || x110px || x110px || x100px || x100px || [[File:Cocaine analog 231f.svg|x100px]]
|-
|rowspan=2|2α,6β-isomers:<br>'''''(232a—f)'''''
|-
| [[File:Cocaine analog 230a.svg|x110px]] || x110px || x110px || x100px || x90px || [[File:Cocaine analog 232f.svg|x100px]]
|-
|}

{| class="wikitable sortable"
|+6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#60 Page #984 (60th page of article)] §H, Figure 37 & Page #985 (61st page of article) Table 36.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name/WIN number)
! ''R''
! K<sub>i</sub> (nM)<br>[<sup>3</sup>H]WIN 35428 binding
! IC<sub>50</sub> (nM)<br>[<sup>3</sup>H]DA uptake
! Selectivity
uptake/binding
|-
| || Cocaine || ||32 ± 5<br>338 ± 221||405 ± 91<br>405 ± 91||12.6<br>1.2
|-
| || WIN 35065-2 || ||33 ± 17<br>314 ± 222||373 ± 10||11.3
|-
|rowspan=8| [[File:229 Analogue Scaffold.svg|x140px|]]
|-
| (−)-229a || H ||33 ± 5||161 ± 100||4.9
|-
| 229a || H ||91 ± 10||94 ± 26||1.0
|-
| 229b || Me ||211 ± 23|| - || -
|-
| 229c || Et ||307 ± 28|| - || -
|-
| 229d || ''n''-Pr ||4180 ± 418|| - || -
|-
| 229e || ''n''-Bu ||8580 ± 249|| - || -
|-
| 229f || Bn ||3080 ± 277|| - || -
|-
|rowspan=8| [[File:230 Analogue Scaffold.svg|x140px|]]
|-
| (+)-230a || H ||60 ± 6||208 ± 63||3.5
|-
| 230a || H ||108 ± 14||457 ± 104||4.2
|-
| 230b || Me ||561 ± 64|| - || -
|-
| 230c || Et ||1150 ± 135|| - || -
|-
| 230d || ''n''-Pr ||7240 ± 376|| - || -
|-
| 230e || ''n''-Bu ||19700 ± 350|| - || -
|-
| 230f || Bn ||7590 ± 53|| - || -
|-
|rowspan=5| [[File:231 Analogue Scaffold.svg|x140px|]]
|-
| 231b || Me ||57 ± 5||107 ± 36||1.9
|-
| 231c || Et ||3110 ± 187|| - || -
|-
| 231d || ''n''-Pr ||5850 ± 702|| - || -
|-
| 231f || Bn ||1560 ± 63|| - || -
|-
|rowspan=5| [[File:232 Analogue Scaffold.svg|x140px|]]
|-
| 232b || Me ||294 ± 29||532 ± 136||1.8
|-
| 232c || Et ||6210 ± 435|| - || -
|-
| 232d || ''n''-Pr ||57300 ± 3440|| - || -
|-
| 232f || Bn ||3080 ± 277|| - || -
|-
| || 241 || Bn ||4830 ± 434|| - || -
|}

{| class="wikitable mw-collapsible"
|+{{nowrap|Benzylidene derivatives of 6-alkyl-3-benzyltropanes{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#60 Page #984 (60th page of article)] Scheme 56.}}}}
! Sub-category<br>(''S. Singh compound #'')
! a<br>''R''=H
! b<br>''R''=Me
! c<br>''R''=Et
! d<br>''R''=''n''-Pr
! e<br>''R''=''n''-Bu
! f<br>''R''=Bn
|-
|rowspan=2|6α-isomers:<br>'''''(237a—f)'''''
|-
|[[File:Cocaine analog 237a.svg|x95px]]||x105px||x110px||x125px||x135px||[[File:Cocaine analog 237f.svg|x135px]]
|-
|rowspan=2|6β-isomers (exo):<br>'''''(238a—f)'''''
|-
|[[File:Cocaine analog 238a.svg|x77px]]||x85px||x85px||x85px||[[File:Cocaine analog 238e.svg|x85px]]||
[[File:Cocaine analog 238f.svg|x105px]]
|-
|rowspan=2|3β-benzyl derivatives:<br>'''''(239a—f)'''''
|-
|[[File:Cocaine analog 239a.svg|x115px]]||x110px||x110px||x130px||x135px||[[File:Cocaine analog 239f.svg|x135px]]
|-
|rowspan=2|intermediate<br>alkylidene esters:<br>'''''(240a—f)'''''
|-
|[[File:Cocaine analog 240a.svg|x115px]]||x115px||x115px||x130px||x135px||[[File:Cocaine analog 240f.svg|x135px]]
|-
|}
''[[Social:Nota bene|N.B.]]'' The benzylidene derivatives serve as synthetic intermediates for 6-Alkyl-3-benzyltropanes and have not been assayed for biological activity.  Compounds ''237a'' and ''238a'' are the same compound as both are the parent for either series with a hydrogen saturated in their respective substitution place.

===Direct 2,3-pyrimidino fused===
 {{multiple image
 | direction = vertical
 | image1 = Strobamine.svg
 | width1 = 280
 | caption1 = ''above:'' Strobamine, a DARI functional cocaine analog with structural semblance.<ref>[http://www.arkat-usa.org/get-file/36494/ Enantioselective synthesis of strobamine and its analogues] Xing Zhang et al. Center for Organic and Medicinal Chemistry, Research Triangle Institute. Issue in Honor of Prof. James M.Cook ARKIVOC 2010 (iv)96-103</ref> Compare the phenyltropane length tropane C2 & C3 functional group fusion variant.<ref>[https://books.google.com/books?id=rjtEwOFM5owC&dq=Strobamine&pg=PA17 The Alkaloids; Vol. 44, Geoffrey Cordell]</ref><br><br>''below:'' Chalcostrobamine
 | image2 = Chalcostrobamine Structure.svg 
 | width2 = 190
 }}
''cf.'' strobamine (at right) for a more efficacious compound as like the below.
{| class="wikitable sortable"
|+2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.<ref name="AppellDunn2002">{{cite journal|last1=Appell|first1=Michael|last2=Dunn|first2=William J.|last3=Reith|first3=Maarten E.A.|last4=Miller|first4=Larry|last5=Flippen-Anderson|first5=Judith L.|title=An Analysis of the Binding of Cocaine Analogues to the Monoamine Transporters Using Tensor Decomposition 3-D QSAR|journal=Bioorganic & Medicinal Chemistry|volume=10|issue=5|year=2002|pages=1197–1206|issn=0968-0896|doi=10.1016/S0968-0896(01)00389-3|pmid=11886784}}</ref><br>(Binding values @ biogenic amine transporters (BATs) for rigid and semi-rigid analogs)
! Structure
! alphanumeric<br>assignation
! ''R<sub>1</sub>''
! ''R<sub>2</sub>''
! hDAT<br>IC<sub>50</sub> (nM)
! hSERT<br>IC<sub>50</sub> (nM)
! hNET<br>IC<sub>50</sub> (nM)
|-
|rowspan=3|[[File:2,3-fused pyrimidino cocaine analogue 3a.svg|230px]]
|-
| (—)-3a || H || C<sub>6</sub>H<sub>5</sub> || 58,300 (20,200) || 6140 (3350) || NA
|-
| (+)-3a || H || C<sub>6</sub>H<sub>5</sub>  || 48,700 (20,100) || 6030 (3400) || NA
|-
|rowspan=3|[[File:2,3-fused pyrimidino cocaine analogue 3b.svg|190px]]
|-
| (—)-3b || H || NH<sub>2</sub> || NA || NA || NA
|-
| (+)-3b || H || NH<sub>2</sub> || NA || NA || NA
|-
|rowspan=3|[[File:2,3-fused pyrimidino cocaine analogue 3c.svg|190px]]
|-
| (—)-3c || H || CH<sub>3</sub> ||NA||NA||NA
|-
| (+)-3c || H || CH<sub>3</sub> ||NA||NA||NA
|-
|rowspan=3|[[File:2,3-fused pyrimidino cocaine analogue 3d.svg|150px]]
|-
| (—)-3d || H || H ||NA||NA||NA
|-
| (+)-3d || H || H ||NA||NA||NA
|-
| [[File:2,3-fused pyrimidino cocaine analogue 3e.svg|240px]] ||(+/—)-3e || C<sub>6</sub>H<sub>5</sub> || C<sub>6</sub>H<sub>5</sub> || 30,000 (11,200) || 3650 (1700) || NA
|}
*<small>"'''NA'''" = "no affinity", ''e.g.'' unquantifiable.</small>

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.<ref name="AppellDunn2002"/>

===Piperidine cocaine-homologues===
[[File:Methyl (1R,2R,3S,5S)-8-methyl-3-(tricyclo(9.4.0.0³,⁸)pentadeca-1(11),3,5,7,12,14-hexaene-2-carbonyloxy)-8-azabicyclo(3.2.1)octane-2-carboxylate.svg|thumb|right|x200px|Tricyclo benzoyloxy dibenzene cocaine analogue. ''cf.'' benztropine compound #'''277''', tropatepine, ''etc''.<ref name="Carroll"/>]]
{| class="wikitable sortable"
|+Binding potency of piperidine homologues for displacement of [<sup>3</sup>H]WIN 35428{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#62 Page #986 (62nd page of article)] §I, Table 37 & Scheme 58}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! 2''β''-R
! IC<sub>50</sub> (nM)
|-
| || (Cocaine) ||CO<sub>2</sub>CH<sub>3</sub><br>(''i.e.'' CO<sub>2</sub>Me)||249 ± 37
|-
| [[File:Cocaine analog 183a.svg|x150px]] || 183a ||CO<sub>2</sub>CH<sub>3</sub>||2522 ± 4
|-
| [[File:Cocaine analog 242.svg|x120px]] ||  242 || H ||11589 ± 4
|-
| [[File:Cocaine analog 243.svg|x160px]] || 243 || CO<sub>2</sub>CH<sub>3</sub> ||8064 ± 4
|}
<small>''cf.'' phenyltropane piperidine-homologues for compounds with a more optimized conformation that yield higher affinities when binding to MAT.</small>

===Cocaine [[Biology:Hapten|hapten]] analogues===
[[File:Cocaine analog GNC.svg|right|thumb|x200px|"'''GNC'''", a cocaine analog designed to minimize the formation of noncocaine-like structures through its chemical coupling to the Ad proteins; all while maintaining the element of its antigenic determinant from the moiety of cocaine.<ref>{{cite journal | pmc = 3048190 | pmid=21206484 | doi=10.1038/mt.2010.280 | volume=19 | issue=3 | title=Cocaine analog coupled to disrupted adenovirus: a vaccine strategy to evoke high-titer immunity against addictive drugs | journal=Mol Ther | pages=612–9 | last1 = Hicks | first1 = MJ | last2 = De | first2 = BP | last3 = Rosenberg | first3 = JB | last4 = Davidson | first4 = JT | last5 = Moreno | first5 = AY | last6 = Janda | first6 = KD | last7 = Wee | first7 = S | last8 = Koob | first8 = GF | last9 = Hackett | first9 = NR | last10 = Kaminsky | first10 = SM | last11 = Worgall | first11 = S | last12 = Toth | first12 = M | last13 = Mezey | first13 = JG | last14 = Crystal | first14 = RG | year=2011}}</ref>]]
{| class="wikitable sortable"
|+Cocaine analogs which elicit noncatalytic antibodies{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#90 Page #1,014 (90th page of article)] §VIII, A. Figure 59.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! 2''β''-R
|-
| [[File:CocaineNoncatalyticHapten394.svg|200px]] ||394<br>(GNC)<sup>'''ɑ'''</sup>||CO<sub>2</sub>(CH<sub>2</sub>)<sub>5</sub>CO<sub>2</sub>H
|-
| [[File:CocaineNoncatalyticHapten395.svg|240px]] ||395<br>(Succinyl Norcocaine)<ref>{{cite journal | pmc = 3142961 | pmid=21796226 | doi=10.1358/dof.2010.035.04.1474292 | volume=35 | issue=4 | title=Active immunotherapy for the Treatment of Cocaine Dependence | journal=Drugs of the Future | pages=301–306 | last1 = Kinsey | first1 = BM | last2 = Kosten | first2 = TR | last3 = Orson | first3 = FM | year=2010}}</ref>||CO<sub>2</sub>CH<sub>3</sub>
|-
| [[File:Cocaine hapten GNE.svg|210px]] ||GNE<sup>'''b'''</sup><ref>{{cite journal | pmc = 3306868 | pmid=21918504 | doi=10.1038/npp.2011.200 | volume=37 | issue=5 | title=Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects | journal=Neuropsychopharmacology | pages=1083–91 | last1 = Wee | first1 = S | last2 = Hicks | first2 = MJ | last3 = De | first3 = BP | last4 = Rosenberg | first4 = JB | last5 = Moreno | first5 = AY | last6 = Kaminsky | first6 = SM | last7 = Janda | first7 = KD | last8 = Crystal | first8 = RG | last9 = Koob | first9 = GF | year=2011}}</ref><br><small>including carrier proteins:<br>GNE-FLiC<br>GNE-KLH<br>GNE-BSA</small>||
|-
| [[File:CocaineNoncatalyticHapten396.svg|200px]]||396||CONH(CH<sub>2</sub>)<sub>5</sub>CO<sub>2</sub>H
|}
*<sup>'''ɑ'''</sup><small>6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo <nowiki>[3.2.1]</nowiki> octane-2-carbonyloxy-hexanoic acid</small>
*<sup>'''b'''</sup><small>6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo <nowiki>[3.2.1]</nowiki> octane-2-carboxamido-hexanoic acid</small>
[[File:Cocaine analog 400 intermediate.svg|right|thumb|x150px|Tetrahedral-intermediate cocaine-hapten compound #'''400''']]
{| class="wikitable sortable"
|+Cocaine transition state analogues (TSAs) which generate catalytic antibodies{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#92 Page #1,016 (92nd page of article)] Figure 60.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''R''
|-
|rowspan=8|[[File:Cocaine analog 401.svg|200px]]
|-
| 401a || CH<sub>3</sub>
|-
| 401b || (CH<sub>2</sub>)<sub>5</sub>CO<sub>2</sub>H
|-
| 401c || CH<sub>2</sub>CO<sub>2</sub>H
|-
| 401d || COCH<sub>2</sub>CH<sub>2</sub>CO<sub>2</sub>H
|-
| 401e || H
|-
| 401f || CH<sub>2</sub>CH<sub>2</sub>Br
|-
| 385g || (CH<sub>2</sub>)<sub>2</sub>NHCO(CH<sub>2</sub>)<sub>2</sub>CONH<sub>2</sub>
|-
|rowspan=6|[[File:Cocaine analog 402.svg|200px]]
|-
| 402a || O(CH<sub>2</sub>)<sub>4</sub>NHCO(CH<sub>2</sub>)<sub>2</sub>CO<sub>2</sub>N(CO<sub>2</sub>)<sub>2</sub>C<sub>6</sub>H<sub>4</sub>
|-
| 402b || OH
|-
| 402c || O(CH<sub>2</sub>)<sub>2</sub>(''p''-NH<sub>2</sub>C<sub>6</sub>H<sub>4</sub>)
|-
| 402d || NH(CH<sub>2</sub>)<sub>5</sub>CO<sub>2</sub>H
|-
| 402e || O(CH<sub>2</sub>)<sub>4</sub>NHCO(CH<sub>2</sub>)<sub>2</sub>CONH<sub>2</sub>
|-
|rowspan=5|[[File:Cocaine analog 403.svg|220px]]
|-
| 403a || NH<sub>2</sub>
|-
| 403b || NHCOCH<sub>2</sub>Br
|-
| 403c || NHCO(CH<sub>2</sub>)<sub>3</sub>CO<sub>2</sub>H
|-
| 403d || (CH<sub>2</sub>)<sub>3</sub>NHCO(CH<sub>2</sub>)<sub>2</sub>CONH<sub>2</sub>
|}
Cocaine haptens that create catalytic anti-bodies require transitional states as affected ''in vivo''. Monoclonal antibodies generated against [[Biology:Bovine serum albumin|BSA]]-coupled '''402e''' accelerated the rate of cocaine hydrolysis by ~23,000x and eliminated the reinforcing effects of cocaine administration in rats.<ref>[https://www.google.com/patents/US6566084 Catalytic antibodies against cocaine and methods of using and producing same] Google patents US 6566084 B1</ref><ref name="DengBharat2004">{{cite journal|last1=Deng|first1=Shixian|last2=Bharat|first2=Narine|last3=de Prada|first3=Paloma|last4=Landry|first4=Donald W.|title=Substrate-assisted antibody catalysis|journal=Organic & Biomolecular Chemistry|volume=2|issue=3|year=2004|pages=288–90|issn=1477-0520|doi=10.1039/b314264g|pmid=14747854}}</ref><ref>{{cite journal |last1=Yang |first1=G. |last2=Chun |first2=J. |last3=Arakawa-Uramoto |first3=H. |last4=Wang |first4=X. |last5=Gawinowicz |first5=M. A. |last6=Zhao |first6=K. |last7=Landry |first7=D. W. |title=Anti-Cocaine Catalytic Antibodies: A Synthetic Approach to Improved Antibody Diversity |journal=Journal of the American Chemical Society |date=1 January 1996 |volume=118 |issue=25 |pages=5881–5890 |doi=10.1021/ja953077}}</ref><ref>{{cite journal |last1=Mets |first1=B. |last2=Winger |first2=G. |last3=Cabrera |first3=C. |last4=Seo |first4=S. |last5=Jamdar |first5=S. |last6=Yang |first6=G. |last7=Zhao |first7=K. |last8=Briscoe |first8=R. J. |last9=Almonte |first9=R. |last10=Woods |first10=J. H. |last11=Landry |first11=D. W. |title=A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats |journal=Proceedings of the National Academy of Sciences |date=18 August 1998 |volume=95 |issue=17 |pages=10176–10181 |doi=10.1073/pnas.95.17.10176|pmid=9707620 |pmc=21481 |bibcode=1998PNAS...9510176M |doi-access=free }}</ref>

{| class="wikitable"
|+ Anti-idiotypic & butyl-cholinesterase mediated immunopharmacotherapy cocaine analogs<ref>{{cite journal | pmc = 3295240 | pmid=12878327 | volume=1638 | issue=3 | title=Inhibition of cocaine binding to the human dopamine transporter by a single chain anti-idiotypic antibody: its cloning, expression, and functional properties | journal=Biochim Biophys Acta | pages=257–66 | last1 = Ho | first1 = M | last2 = Segre | first2 = M | doi=10.1016/s0925-4439(03)00091-7 | year=2003}}</ref>
|-
! K1-KLH/BSA<ref>{{cite journal | pmc = 2326984 | pmid=10809958 | volume=100 | issue=1 | title=Exploring the feasibility of an anti-idiotypic cocaine vaccine: analysis of the specificity of anticocaine antibodies (Ab1) capable of inducing Ab2beta anti-idiotypic antibodies | journal=Immunology | pages=48–56 | last1 = Schabacker | first1 = DS | last2 = Kirschbaum | first2 = KS | last3 = Segre | first3 = M | doi=10.1046/j.1365-2567.2000.00004.x | year=2000}}</ref> !! K2-KLH/BSA
|-
| [[File:K1-KLH-BSA.svg|x200px]] || [[File:K2-KLH-BSA.svg|x110px]]
|}

==Structural/Functional intermediate analogues==

===Piperidine Analogues===

* [[Chemistry:JZ-IV-10|JZ-IV-10]] (a "[[Chemistry:Modafinil|Modafinil]] hybrid" with nocaine.<ref name="ZhouHe2004">{{cite journal|last1=Zhou|first1=Jia|last2=He|first2=Rong|last3=Johnson|first3=Kenneth M.|last4=Ye|first4=Yanping|last5=Kozikowski|first5=Alan P.|title=Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization|journal=Journal of Medicinal Chemistry|volume=47|issue=24|year=2004|pages=5821–5824|issn=0022-2623|doi=10.1021/jm040117o|pmid=15537337|pmc=1395211}}</ref> ''cf.'' [[Chemistry:Modafinil#Structural analogues|List of modafinil analogues]])
[[File:JZ-IV-10 chemical structure.png|x150px]]
* [[Chemistry:(+)-CPCA|Nocaine]]
[[File:(+)-CPCA.svg|x100px]]

A somewhat recent occurrence among tentative modern folklore which has traversed the circling of rumors mostly confined to the likes of universities and popular culture trivia has been that cocaine is one element, or molecule increment of weight or charge etc., away from the molecular structure of sugar.<ref>[http://skeptics.stackexchange.com/questions/20216/is-sugar-one-element-away-from-cocaine-or-any-other-drug Skeptics Stack Exchange: Is sugar one element away from cocaine (or any other drug?)]</ref> Though such a statement is false as a general pretense, there is a dextrose based super-structure that has a vaguely similar overlay with cocaine which is "benzoyl-''beta''-<small>D</small>-glucoside."
*[[Chemistry:Benzoyl-beta-D-glucoside|'''Benzoyl-''beta''-<small>D</small>-glucoside''']]
[[File:Benzoyl-beta-D-glucoside.svg|x110px]]

===Benztropine (3α-Diphenylmethoxy Tropane) Analogues===
{| class="wikitable sortable"
|+3α-Diphenylmethoxy tropanes<br>(Benztropine analog affinities binding to DAT & DA uptake){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#63 Page #987 (63rd page of article)] §IV, Figure 39 & Page #988 (64th page of article) Table 38.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''R''
! ''R′''
! ''K<sub>i</sub>'' (nM)<br>[<sup>3</sup>H]WIN 35428 binding
! IC<sub>50</sub> (nM)<br>[<sup>3</sup>H]DA
uptake
! Selectivity
uptake/binding
|-
| || (Cocaine) || || ||388 ± 47|| - || -
|-
| || (GBR 12909) || || ||11.6 ± 31|| - || -
|-
|rowspan=29|[[File:Cocaine analog 249-251.svg|200px]]
|-
| (Benztropine) || H || H ||118 ± 9||403 ± 115||3.4
|-
| 249a || 4′-F || H ||32.2 ± 10|| 48 ||1.5
|-
| 249b<br>(AHN 1-055) || 4′-F || 4′-F ||11.8 ± 1|| 71 ||6.0
|-
| 249c || 3′,4′-di-F || H ||27.9 ± 11||181 ± 45.7||6.5
|-
| 249d || 4′-Cl || H ||30.0 ± 12|| 115 ||3.8
|-
| 249e || 4′-Cl || 4′-Cl ||20.0 ± 14|| 75 ||3.8
|-
| 249f || 3′,4′-di-Cl || H ||21.1 ± 19|| 47 ||2.2
|-
| 249g || 3′,4′-di-Cl || F ||18.9 ± 14|| 24 ||1.3
|-
| 249h || 4′-Br || H ||37.9 ± 7|| 29 ||0.8
|-
| 249i || 4′-Br || 4′-Br || 91.6 || 34 ||0.4
|-
| 249j || 4′-NO<sub>2</sub> || H ||197 ± 8|| 219 ||1.1
|-
| 249k || 4′-CN || H ||196 ± 9|| 222 ||1.1
|-
| 249l || 4′-CF<sub>3</sub> || H ||635 ± 10|| 2155 ||3.4
|-
| 249m || 4′-OH || H ||297 ± 13|| 677 ||2.3
|-
| 249n || 4′-OMe || H ||78.4 ± 8|| 468 ||6.0
|-
| 249o || 4′-OMe || 4′-OMe ||2000 ± 7|| 2876 ||1.4
|-
| 249p || 4′-Me || H ||187 ± 5|| 512 ||2.7
|-
| 249q || 4′-Me || 4′-Me ||420 ± 7|| 2536 ||6.0
|-
| 249r || 4′-Et || H ||520 ± 8|| 984 ||1.9
|-
| 249s || 4′-''t''-Bu || H || 1918 || 4456 ||2.3
|-
| 250a || 3′-F || H ||68.5 ± 12||250 ± 64.7||3.6
|-
| 250b || 3′-F || 3′-F ||47.4 ± 1||407 ± 63.9||8.6
|-
| 250c || 3′-Cl || H ||21.6 ± 7||228 ± 77.1||10.5
|-
| 250d || 3′-CF<sub>3</sub> || H ||187 ± 5||457 ± 72.0||2.4
|-
| 251a || 2′-F || H ||50.0 ± 12||140 ± 17.2||2.8
|-
| 251b || 2′-Cl || H ||228 ± 9||997 ± 109||4.4
|-
| 251c || 2′-Me || H ||309 ± 6||1200 ± 1.64||3.9
|-
| 251d || 2′-NH<sub>2</sub> || H ||840 ± 8||373 ± 117||0.4
|}
{| class="wikitable sortable"
|+3α-Diphenylmethoxy-2β-carbomethoxybenztropine<br>(Benztropine affinities to DAT & 5-HTT in [[Biology:Crab-eating macaque|cynomologous monkey]] [[Biology:Striatum|caudate-putamen]]){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#63 Page #987 (63rd page of article)] Figure 40, Page #988 (64th page of article) §B & Page #989 (65th page of article) Table 39.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''R''
! ''R′''
! IC<sub>50</sub> (nM)<br>DAT<br>(Binding of [<sup>3</sup>H]WIN 35428)
! IC<sub>50</sub> (nM)<br>5-HTT<br>(Binding of [<sup>3</sup>H]Citalopram)
! Selectivity<br>5-HTT/DAT
|-
| || (benztropine) || || ||312 ± 1.1 || 24100 ± 14800||77.2
|-
| || (WIN 35428) || || ||12.9 ± 1.1||160 ± 20||12.4
|-
| || ''R''-256 || || ||2040 ± 283||1460 ± 255||0.7
|-
|rowspan=13|[[File:Cocaine analog 257.svg|200px]]
|-
| ''S''-257a || H || H ||33.5 ± 4.5||10100 ± 1740||301
|-
| ''S''-257b || H || F ||13.2 ± 1.9||4930 ± 1200||373
|-
| ''S''-257c<br>(difluoropine) || F || F ||10.9 ± 1.2||3530 ± 1480||324
|-
| ''S''-257d || H || Cl ||15.8 ± 0.95||5960 ± 467||377
|-
| ''S''-257e || Cl || Cl ||91.4 ± 0.85||3360 ± 1480||36.8
|-
| ''S''-257f || H || Br ||24.0 ± 4.6||5770 ± 493||240
|-
| ''S''-257g || Br || Br ||72.0 ± 3.65||2430 ± 339||33.7
|-
| ''S''-257h || H || I ||55.9 ± 10.3||9280 ± 1640||166
|-
| ''S''-257i || Br || I ||389 ± 29.4||4930 ± 82||12.7
|-
| ''S''-257j || I || I ||909 ± 79||8550 ± 442||9.4
|-
| ''S''-257k || H || Me ||49.5 ± 6.0|| 13200 ||266
|-
| ''S''-257l || Me || Me ||240 ± 18.4||9800 ± 2680||40.8
|}
{| class="wikitable sortable"
|+''N''-Modified 2-carbomethoxybenztropines<br>(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#63 Page #987 (63rd page of article)] Figure 41, Page #989 (65th page of article) §C & Page #990 (66th page of article) Table 40.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''R''
! n
! IC<sub>50</sub> (nM)<br>DAT<br>(Binding of [<sup>3</sup>H]WIN 35428)
! IC<sub>50</sub> (nM)<br>5-HTT<br>(Binding of [<sup>3</sup>H]Citalopram)
! Selectivity<br>5-HTT/DAT
|-
|rowspan=7|[[File:Cocaine analog 258.svg|300px]]
|-
| 258a || || ||20.3 ± 3.5|| - || -
|-
| 258b || H || <sub>1</sub> ||223 ± 53||4970 ± 700||22.3
|-
| 258c || H || <sub>3</sub> ||22.0 ± 11.9||19.7 ± 3||0.9
|-
| 258d || Br || <sub>3</sub> ||80.2 ± 8.8||234 ± 0.5||2.9
|-
| 258e || I || <sub>3</sub> ||119 ± 11||2200 ± 1250||18.5
|-
| 258f || H || <sub>5</sub> ||99.0 ± 28||550 ± 63||5.5
|-
| || 259 ||  ||  ||616 ± 88||55200 ± 20000||89.3
|}

{| class="wikitable sortable"
|+''N''-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes<br>(Benztropine affinities to DAT & 5-HTT){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#64 Page #988 (64th page of article)] Figure 42, Page #990 (66th page of article) §2 & Page #992 (68th page of article) Table 41.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
! ''R''
! ''K<sub>i</sub>'' (nM)<br>DAT<br>(Binding of [<sup>3</sup>H]WIN 35428)
! IC<sub>50</sub> (nM)<br>5-HTT<br>(Uptake of [<sup>3</sup>H]DA)
! Selectivity<br>uptake/binding
|-
|rowspan=23|[[File:Cocaine analog 260-265.svg|200px]]
|-
| 260<br>(AHN 2-003) || H ||11.2 ± 11|| 9.7 ||0.9
|-
| 261a || 3-phenylpropyl ||41.9 ± 11|| 230 ||5.5
|-
| 261b || indole-3-ethyl ||44.6 ± 11|| 1200 ||26.9
|-
| 261c || 4-phenylbutyl ||8.51 ± 14|| 39 ||4.6
|-
| 261d || 4-(4′-nitrophenyl)butyl ||20.2 ± 11|| 650 ||32.2
|-
| 261e || 3-(4′-fluorophenyl)propyl ||60.7 ± 12|| - || -
|-
| 262a || ''n''-butyl ||24.6 ± 8|| 370 ||15.0
|-
| 262b || cyclopropylmethyl ||32.4 ± 9|| 180 ||5.5
|-
| 262c || allyl ||29.9 ± 10|| 14 ||0.5
|-
| 262d || benzyl ||82.2 ± 15|| 290 ||3.5
|-
| 262e || 4-fluorobenzyl ||95.6 ± 10|| 200 ||2.1
|-
| 262f || cinnanyl ||86.4 ± 12|| 180 ||2.1
|-
| 262g || [bis(4-fluorophenyl)methoxy]ethyl ||634 ± 23|| - || -
|-
| 262h || [(4-nitrophenyl)phenylmethoxy]ethyl ||57.0 ± 17|| - || -
|-
| 263 || acetyl || 2340 || 4600 ||2.0
|-
| 264 || formyl ||2020 ± 13|| 5400 ||2.7
|-
| 265a || tosyl || 0%<sup>'''ɑ'''</sup> || - || -
|-
| 265b || mesyl || 18%<sup>'''ɑ'''</sup> || - || -
|-
| (AHN 2-005)<ref name="LolandDesai2007">{{cite journal|last1=Loland|first1=C. J.|last2=Desai|first2=R. I.|last3=Zou|first3=M.-F.|last4=Cao|first4=J.|last5=Grundt|first5=P.|last6=Gerstbrein|first6=K.|last7=Sitte|first7=H. H.|last8=Newman|first8=A. H.|last9=Katz|first9=J. L.|last10=Gether|first10=U.|title=Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors|journal=Molecular Pharmacology|volume=73|issue=3|year=2007|pages=813–823|issn=0026-895X|doi=10.1124/mol.107.039800|pmid=17978168|s2cid=5061034}}</ref> || CH<sub>2</sub>CH=CH<sub>2</sub> || - || - || -
|-
| (JHW 007)<ref name="LolandDesai2007"/> || CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>CH<sub>3</sub> || - || - || -
|-
| (GA 2-99)<ref name="LolandDesai2007"/> || CH<sub>2</sub>CH<sub>2</sub>NH<sub>2</sub> || - || - || -
|-
| (GA 103)<ref name="LolandDesai2007"/> || CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>Ph || - || - || -
|-
| [[File:Cocaine analog 266.svg|200px]] || 266 ||  ||108 ± 12|| 130 ||1.2
|-
|}
<sup>'''ɑ'''</sup><small>Inhibition at 10 μM</small>
{| class="wikitable sortable"
|+8-Oxa-2-carbomethoxy norbenztropines<br>(8-Oxanortropane benztropine analog affinities to DAT & 5-HTT){{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#64 Page #988 (64th page of article)] Figure 43, Page #992 (68th page of article) §3 & Table 42.}}
! Compound
! S. Singh's<br>alphanumeric<br>assignation<br>(name)
!
! IC<sub>50</sub> (nM)<br>DAT<br>(Binding of [<sup>3</sup>H]WIN 35428)
! IC<sub>50</sub> (nM)<br>5-HTT<br>(Binding of [<sup>3</sup>H]Citalopram)
|-
| [[File:Cocaine analog 268.svg|200px]] || ''R/S''-268 || 2β,3β || >10000 || >1660
|-
| || ''R/S''-269 || 2α,3β || 20300 || >1660
|-
| || ''R/S''-270 || 2α,3α || 22300 || >1660
|-
| [[File:Cocaine analog 271.svg|200px]] || ''R/S''-271 || 2β,3α || 520 || >1660
|}
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 3α-Diphenylmethoxytropane Analogues of Cocaine 
|-
! [[Chemistry:Benzatropine|Benzatropine]] !! [[Chemistry:Etybenzatropine|Etybenzatropine]] !! [[Chemistry:Difluoropine|Difluoropine (O-620)]] !! PG01053 !! 276 !! 277
|-
| [[File:Benzatropine.svg|x165px|Benzatropine]] || x165px|Etybenzatropine || x185px|Difluoropine is a stimulant drug which acts as a more selective dopamine reuptake inhibitor than cocaine. || x165px|PG01053 || x165px|Compound '''276''' || [[File:Benztropine 277.svg|x165px|Compound '''277''']]
|-
! MFZ 4-86 !! MFZ 2-71 !! 3-CPMT !! JHW 007-d9<ref>{{cite journal |last1=Tanda |first1=Gianluigi |last2=Newman |first2=Amy Hauck |last3=Ebbs |first3=Aaron L. |last4=Tronci |first4=Valeria |last5=Green |first5=Jennifer L. |last6=Tallarida |first6=Ronald J. |last7=Katz |first7=Jonathan L. |title=Combinations of Cocaine with Other Dopamine Uptake Inhibitors: Assessment of Additivity |journal=Journal of Pharmacology and Experimental Therapeutics |date=September 2009 |volume=330 |issue=3 |pages=802–809 |doi=10.1124/jpet.109.154302|pmid=19483071 |pmc=2729796 }}</ref> !! GA 103 !! AHN 1-055
|-
| [[File:MFZ 4-86.svg|x165px]] || x165px || x165px|3-CPMT || x165px|Deuterium labeled radio-ligand of benztropine analog [[JHW-007; a di-''para''-fluoro benztropine, and hybrid between benzatropine & difluoropine (with fluorine groups in the former to breach the difference or the latter being descarbmethoxy to approach identification with the former)]] || x165px|N-phenylpropyl bis-4-fluorobenztropine. || [[File:AHN 1-055 Structure.svg|x165px|The 4′,4′-bisfluorinated analogue of benztropine.]]
|}

The binding of benztropine analogues to the [[Biology:Dopamine transporter|DAT]] differs significantly from that of cocaine and the phenyltropanes. Benztropines are considered to be "atypical" DAT ligands because they stabilize the DAT in an inward-facing (closed-to-out) conformation, whereas cocaine and the phenyltropanes stabilize the DAT in an outward-facing (open-to-out) conformation.  This difference in DAT binding may be responsible for the lack of cocaine-like behavioral effects observed in animal and human studies of the benztropine analogues and other “atypical” DAT inhibitors. <ref>{{cite journal | pmc = 3684841 | pmid=23568856 | doi=10.1124/jpet.111.191056 | volume=346 | issue=1 | title=Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates | year=2013 | journal=J. Pharmacol. Exp. Ther. | pages=2–10 | last1 = Schmitt | first1 = KC | last2 = Rothman | first2 = RB | last3 = Reith | first3 = ME}}</ref> Studies of the structure-activity relationships of benztropine have shown that DAT affinity and selectivity over other monoamine transporters is enhanced by 4′,4′-difluorination. Modification of the tropane n-substituent was found to mitigate the anticholinergic effects of benztropine analogues by reducing M1 affinity.<ref name=Rothman>{{cite journal | last1 = Rothman | first1 = RB | last2 = Baumann | first2 = MH | last3 = Prisinzano | first3 = TE | last4 = Newman | first4 = AH | year = 2008 | title = Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction | journal = Biochem Pharmacol | volume = 75 | issue = 1| pages = 2–16 | doi = 10.1016/j.bcp.2007.08.007 | pmid = 17897630 | pmc = 2225585 }}</ref><ref name=Runyon>{{cite journal | last1 = Runyon | first1 = SP | last2 = Carroll | first2 = FI | year = 2006 | title = Dopamine transporter ligands: recent developments and therapeutic potential | journal = Curr Top Med Chem | volume = 6 | issue = 17| pages = 1825–43 | doi = 10.2174/156802606778249775 | pmid = 17017960 }}</ref>

===Tropanyl Isoxazoline Analogues===
{| role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Tropanyl-Δ<sup>2</sup>-isoxazoline derivatives<ref>C. Dallanoce et al. - Bioorg. Med. Chem. 20 (2012) 6344-6355</ref>
|-
! 4a !! 4c !! 5a !! 5c 
|-
| [[File:Dallanoce 4a.svg|x200px]]||x210px||x190px||[[File:Dallanoce 5c.svg|x210px]]
|-
! 6a !! 6b !! 6c !! 7a 
|-
| [[File:Dellancoe 6a.svg|x170px]]||x170px||x170px||[[File:Dallanoce 7a.svg|x170px]]
|-
! 7b !! 7c !! 8a !! 8b 
|-
| [[File:Dallanoce 7b.svg|x170px]]||x190px||x190px||[[File:Dallanoce 8b.svg|x170px]]
|-
! 8c !! 9a !! 9b !! 9c 
|-
| [[File:Dallanoce 8c.svg|x170px]]||x170px||x170px||[[File:Dallanoce 9c.svg|x190px]]
|-
! 10a !! 10b !! 10c !! 11a 
|-
| [[File:Dallanoce 10a.svg|x170px]]||x170px||x190px||[[File:Dallanoce 11a.svg|x180px]]
|-
! 11b !! 12a !! 12b 
|-
| [[File:Dallanoce 11b.svg|x180px]]||x180px||[[File:Dallanoce 12b.svg|x180px]]
|} <!-- End of the table -->

Compound '''7a''' (''3′-methoxy-8-methyl-spiro(8-azabicyclo(3.2.1)octane-3,5′(4′H)-isoxazole'') allosterically enhances SERT binding of other reuptake ligands. Compound '''7a ''' construed as a potentiating allosteric effect (by unveiling occluded configured serotonin uptake-area ligand-site on surface of transporter that allows for binding by exogenous ligand, when SERT is otherwise conformed in a transitional manner where a SERT ligand cannot bind, this effect with compound in question occurs) at concentrations of 10μM—30μM (wherein it acts by interconverting the conformational state of unexposed SERTs to ones exposing the SSRI binding site via a shift to the equilibrium of the MAT) while exerting an inhibitory orthosteric effect when concentrations reach >30μM and above.<br><br>'''7a''' is the only known compound to allosterically modulate SERT in such a way within ''in vitro'' conditions ([[Chemistry:Tianeptine|tianeptine]] has been shown to do similar, but has only shown efficacy doing so in living ''in vivo'' tissue samples). Considering its noncompetitive inhibition of 5-HT transporters decreasing ''V''<sub>max</sub> with small change in the ''K''<small>m</small> for serotonin, putatively stabilizing the cytoplasm-facing conformation of SERT: in such respect it is considered to have the opposite effect profile of the anti-addiction drug [[Biology:Ibogaine|ibogaine]] (save for the function by which its anti-addictive properties are thought to be mediated, ''i.e.'' α<sub>3</sub>β<sub>4</sub> nicotinic channel blockage. ''cf.'' 18-Methoxycornaridine for such nicotinergic activity without the likewise SERT affinity).<ref name="DallanoceCanovi2012">{{cite journal|last1=Dallanoce|first1=Clelia|last2=Canovi|first2=Mara|last3=Matera|first3=Carlo|last4=Mennini|first4=Tiziana|last5=De Amici|first5=Marco|last6=Gobbi|first6=Marco|last7=De Micheli|first7=Carlo|title=A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake|journal=Bioorganic & Medicinal Chemistry|volume=20|issue=21|year=2012|pages=6344–6355|issn=0968-0896|doi=10.1016/j.bmc.2012.09.004|pmid=23022052}}</ref><br><br>Compound '''11a''' possesses similar effects, but acts on the DAT. Similarly, such peripheral DAT considerations (when, as often is, considered conformational rather than otherwise explained as being electrostatic) may constitute the difference in affinity, through allosertic occulsion, between cyclopentyl-ruthenium phenyltropane in its difference from the tricarbonyl-chromium

===Alicyclic Amine Analogues===
{| class="wikitable"
|-
! [[Chemistry:EXP-561|EXP-561]] !! [[Chemistry:Butyltolylquinuclidine|Butyltolylquinuclidine]]
|-
| [[File:EXPfivesixone.png|x160px]] || [[File:Butyltolylquinuclidine.png|x130px]]
|}

===Dihydroimidazoles===
[[File:Mazindol analogs 2.svg|thumb|right|200px|Possible substitutions of the Mazindol molecular structure.]]
See: [[Chemistry:Mazindol#Analogues|List of Mazindol analogues]]

Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for ''e.g.'' Beagles{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#87 Page #1,011 (87th page of article)] §VII (7) 1st ¶.}}) tetracyclic dopamine reuptake inhibitor (of somewhat spurious classification in the former).

It is a loosely functional analog used in cocaine research; due in large part to [[Chemistry:N-Ethylmaleimide|''N''-Ethylmaleimide]] being able to inhibit approximately 95% of the specific binding of [<sup>3</sup>H]Mazindol to the residues of the MAT binding site(s), however said effect of 10 [[Physics:Molar concentration#millimolar|mM]] ''N''-Ethylmaleimide was prevented in its entirety by just 10 ''μ''M cocaine. Whereas neither 300 ''μ''M dopamine or <small>D</small>-amphetamine afforded sufficient protection to contrast the efficacy of cocaine.{{efn|<ref name="Singh2"/> ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#45 Page #969 (45th page of article)] 2nd (right-side) column 2nd ¶.}}<br>

==Local anesthetics (not usually CNS stimulants)==
 {{multiple image
 | direction = vertical
 | image1 = Amylocaine.svg
 | width1 = 220
 | caption1 = [[Chemistry:Amylocaine|Amylocaine]], or Stovaine (above), the first synthetically constructed local anesthetic. Compare structure to [[Chemistry:Dimethylaminopivalophenone|dimethylaminopivalophenone]] (below), an analgesic (opioid). Cocaine's classification as a narcotic under {{wipe|United States}} legal code, as has been stretched to be medicinally rationalized such when defining terms very broadly (due to its topical numbing affect, hindering pain signals from CNS recognition via local anesthesia) usually considered an exaggeration of traditional medicine naming convention, in this instance between the first synthetic sodium channel blocker and one of the very simplest opioids there remains a measure of apparent structural similarity between the former anesthetic and latter analgesic "narcotic"; despite the highly differing methods of action for the respective 'pain-killing' properties of either.<ref>{{cite journal | last1 = Ruetsch | first1 = YA | last2 = Böni | first2 = T | last3 = Borgeat | first3 = A | date = Aug 2001 | title = From cocaine to ropivacaine: the history of local anesthetic drugs | journal = Curr Top Med Chem | volume = 1 | issue = 3| pages = 175–82 | pmid = 11895133 | doi=10.2174/1568026013395335}}</ref>
 | image2 = 3-(dimethylamino)-2,2-dimethyl-1-phenylpropan-1-one.svg
 | width2 = 220
 }}
In animal studies, certain of the local anesthetics have displayed residual [[Chemistry:Dopamine reuptake inhibitor|dopamine reuptake inhibitor]] properties,<ref name=Wilcox>{{cite journal|last1=Wilcox |first1=K.M. |last2=Kimmel |first2=H.L. |last3=Lindsey |first3=K.P. |last4=Votaw |first4=J.R. |last5=Goodman |first5=M.M. |last6=Howell |first6=L.L. |year=2005 |title=In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys |url=http://research.yerkes.emory.edu/Howell/Synapse58.pdf |journal=Synapse |volume=58 |issue= 4|pages=220–228 |doi=10.1002/syn.20199 |pmid=16206183 |url-status=dead |archive-url=https://web.archive.org/web/20100611201857/http://research.yerkes.emory.edu/Howell/Synapse58.pdf |archive-date=2010-06-11 |citeseerx=10.1.1.327.1264 |s2cid=15631376 }}</ref> although not normally ones that are easily available. These are expected to be more cardiotoxic than phenyltropanes. For example, dimethocaine has behavioral stimulant effects (and therefore not here listed below) if a dose of it is taken that is 10 times the amount of cocaine. Dimethocaine is equipotent to cocaine in terms of its anesthetic equivalency.<ref name=Wilcox/> [[Medicine:Local anesthetic#Treatment of overdose: "Lipid rescue"|Intralipid "rescue"]] has been shown to reverse the cardiotoxic effects of sodium channel blockers and presumably those effects when from cocaine administered intravenously as well.

{| class="wikitable"
|+ List of local anesthetics
|-
! scope="col" | Name
! scope="col" | Other common names
|-
| [[Chemistry:Amylocaine|Amylocaine]] || Stovaine
|-
| [[Chemistry:Articaine|Articaine]] || Astracaine, Carticaine, Septanest, Septocaine, Ultracaine, Zorcaine
|-
| [[Chemistry:Benzocaine|Benzocaine]] || Anbesol, Lanacane, Orajel
|-
| [[Chemistry:Bupivacaine|Bupivacaine]] || Marcaine, Sensorcaine, Vivacaine
|-
| [[Chemistry:Butacaine|Butacaine]] || Butyn
|-
| [[Chemistry:Chloroprocaine|Chloroprocaine]] || Nesacaine
|-
| [[Chemistry:Cinchocaine|Cinchocaine/Dibucaine]] || Cincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
|-
| [[Chemistry:Cyclomethycaine|Cyclomethycaine]] || Surfacaine, Topocaine
|-
| [[Chemistry:Etidocaine|Etidocaine]] || Duranest
|-
| [[Chemistry:Eucaine|Eucaine]] || α-eucaine, β-eucaine
|-
|-
| Fotocaine<ref name="SchoenbergerDamijonaitis2014"/>||
|-
| [[Chemistry:Hexylcaine|Hexylcaine]] || Cyclaine, Osmocaine
|-
| [[Chemistry:Levobupivacaine|Levobupivacaine]] || Chirocaine
|-
| [[Chemistry:Lidocaine|Lidocaine/Lignocaine]] || Xylocaine, Betacain'''e'''
|-
| [[Chemistry:Mepivacaine|Mepivacaine]] || Carbocaine, Polocaine
|-
| [[Chemistry:Meprylcaine|Meprylcaine/Oracaine]] || Epirocain
|-
| [[Chemistry:Metabutoxycaine|Metabutoxycaine]] || Primacaine
|-
| [[Chemistry:Phenacaine|Phenacaine/Holocaine]] || Holocaine
|-
| [[Chemistry:Piperocaine|Piperocaine]] || Metycaine
|-
| [[Chemistry:Pramocaine|Pramocaine/Pramoxine]] || Pramoxine
|-
| [[Chemistry:Prilocaine|Prilocaine]] || Citanest
|-
| [[Chemistry:Propoxycaine|Propoxycaine/Ravocaine]] || Pravocaine, Ranocaine, Blockain
|-
| [[Chemistry:Procaine|Procaine/Novocaine]] || Borocaine (Procaine Borate), Ethocaine
|-
| Proparacaine/Alcaine || Alcaine
|-
| [[Chemistry:Quinisocaine|Quinisocaine]] || Dimethisoquin
|-
| [[Chemistry:Risocaine|Risocaine]] || Propaesin, Propazyl, Propylcain
|-
| [[Chemistry:Ropivacaine|Ropivacaine]] || Naropin
|-
| [[Chemistry:Tetracaine|Tetracaine/Amethocaine]] || Pontocaine, Dicaine
|-
| [[Chemistry:Trimecaine|Trimecaine]] || Mesdicain, Mesocain, Mesokain
|}

==See also==
[[File:Cinnamoylcocaine.svg|thumb|[[Chemistry:Methylecgonine cinnamate|Methylecgonine cinnamate]], an alkaloid widely considered inactive in its own right, but postulated to be active under pyrolysis. (''cf.'' alkylphenyltropane analogue "224e") It is, however, found in patents of active cocaine analogue structures.<ref>{{US patent|6479509}} Patent inventor Frank Ivy Carroll, Assignee: Research Triangle Institute</ref><ref>[https://patentimages.storage.googleapis.com/US6479509B1/US06479509-20021112-C00016.png U.S. patent US6479509 B1 structures given for submission, 5th compound down in image.]</ref>|right|x150px]]
* Coca alkaloids, the ones relating to [[Biology:Biosynthesis of cocaine|cocaine biosynthesis]] include: benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, methylecgonine cinnamate, tropacocaine & truxilline
* [[Biology:Cocaine#Pharmacology|Cocaine metabolites (Human)]], which include: benzoylecgonine (BE), ecgonine methyl ester (EME), ecgonine, norcocaine, ''p''-hydroxycocaine, ''m''-hydroxycocaine, ''p''-hydroxybenzoylecgonine (''p''OHBE) & ''m''-hydroxybenzoylecgonine
* [[Chemistry:Dopaminergic|Dopaminergic]]s
* Federal Analog Act
* [[Chemistry:Pharmacophore|Pharmacophore]]
* Pharmacopoeia
* [[Medicine:Pharmacokinetics|Pharmacokinetics]]
* [[Chemistry:Pharmacodynamics|Pharmacodynamics]]

'''Common analogues to prototypical [[Biology:Dopamine|D]]-[[Chemistry:Monoamine releasing agent|RAs]]:'''
:*[[Chemistry:Substituted amphetamine|Substituted amphetamine]]s
:*[[Chemistry:Substituted cathinone|Substituted cathinone]]s
:*[[Chemistry:Substituted phenethylamine|Substituted phenethylamine]]s
:*[[Chemistry:Substituted phenylmorpholine|Substituted phenylmorpholine]]s
:*Substituted methylenedioxyphenethylamines

==Notes (inclu. specific locations of citations from within references used)==
{{Notelist|20em}}

==References==
{{Reflist}}

==External links==
* [http://www.wipo.int/pctdb/en/wo.jsp?wo=2003099783&IA=WO2003099783&DISPLAY=DESC U. S. Provisional Patent Application listing examples of compounds which are tropanes for prospective use in research]
* [http://www.emory.edu/ACAD_EXCHANGE/2001/octnov/kuharqa.html Article on cocaine analogue research] {{Webarchive|url=https://web.archive.org/web/20060922070754/http://www.emory.edu/ACAD_EXCHANGE/2001/octnov/kuharqa.html |date=2006-09-22 }}
* [http://chemicalland21.com/info/TROPANYL%20COMPOUNDS.htm List of tropanyl type molecules] and their [[CAS Registry Number]]s

{{Phenyltropanes}}
{{Stimulants}}
{{Serotonergics}}
{{Sigmaergics}}
{{Anorectics}}
{{Antidepressants}}
{{Receptor agonists and antagonists}}

{{DEFAULTSORT:Cocaine Analogues}}
[[Category:Euphoriants]]
[[Category:Carboxylate esters]]
[[Category:Methyl esters]]
[[Category:Tropanes]]

{{Sourceattribution|List of cocaine analogues}}