Chemistry:List of cocaine analogues

Short description: none

Top: Cocaine in the chair conformation of the tropane-ring, with only its tropane locants given.

Middle: Cocaine with its numerical substitution position locants.
2′ (6′) = ortho, 3′ (5′) = meta & 4′ = para

Bottom: Alternate two-dimensional molecular diagram of cocaine; shown specifically as a protonated, NH+, hydrochloride, and disregarding 3D stereochemistry

This is a list of cocaine analogues. A cocaine analogue is an (usually) artificial construct of a novel 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 3β-benzoyloxy or similar functionality (the term specifically used usually distinguishes from phenyltropanes, 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:^{[lower-alpha 1]}

stereoisomers of cocaine
3β-phenyl ring substituted analogues
2β-substituted analogues
N-modified analogues of cocaine
3β-carbamoyl analogues
3β-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 total synthesis of cocaine, but modified to alter their effect & QSAR. These include both intracellular sodium channel blocker anaesthetics and stimulant dopamine reuptake inhibitor ligands (such as certain, namely tropane-bridged-excised, piperidines). 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.^{[lower-alpha 2]}

Analogs sensu stricto

Cocaine Stereoisomers

Stereoisomer	S. Singh's alphanumeric assignation	IC₅₀ (nM) [³H]WIN 3542 inhibition to rat striatal membranes Mean error standard ≤5% in all cases	IUPAC nomenclature
R-cocaine (Erythroxyline)		102	methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-pseudococaine (Delcaine, Depsococaine, Dextrocaine, Isococaine, Psicaine.^[2])	172	15800	methyl(1R,2S,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-allococaine	173	6160	methyl(1R,2R,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-allopseudococaine	174	28500	methyl(1R,2S,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
S-cocaine	175	15800	methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-pseudococaine	176	22500	methyl(1S,3R,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allococaine	177	9820	methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allopseudococaine	178	67700	methyl(1S,3S,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate

The structure of cocaine with relevant structural motifs for activity at the dopamine transporter highlighted.

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.^{[lower-alpha 3]}

There are eight stereoisomers of cocaine (excluding mesomers and modifications to the internal portion of the tropane ring).^{[lower-alpha 4]} 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 epimerization. For example, the end product of cocaine biosynthesis contains an axial C2-carbomethoxy moiety which readily undergoes epimerization to the equatorial position via 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.

Arene benzene-ring 2′, 3′, 4′ (5′ & 6′) position (aryl) substitutions

para-substituted benzoylmethylecgonines

Carbon 4′-hydrogen Substitutions (benzene-4′ "*para*" substituted benzoyloxytropanes)^{[lower-alpha 5]}
^{Data-set congruent to, and aggregate with, following tables
IC₅₀ values}
Structure	S. Singh's alphanumeric assignation (name)	4′=R	DAT [³H]WIN 35428	5-HTT [³H]Paroxetine	NET [³H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Cocaine	H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0
non-benzoyloxy analogue comparative ligands _{non-tropane analogue comparative ligands}	11b (WIN 35428) _(nisoxetine) ^(fluoxetine)	F _— ^—	24 ± 4 _{775 ± 20} ^{5200 ± 1270}	690 ± 14 _{762 ± 90} ^{15 ± 3}	258 ± 40 _{135 ± 21} ^{963 ± 158}	28.7 _1.0 ^0.003	10.7 _0.2 ^0.2

	183a	I	2522 ± 4	1052 ± 23	18458 ± 1073	0.4	7.3
	183b	Ph	486 ± 63	-	-	-	-
	183c	OAc	144 ± 2	-	-	-	-
	183d	OH	158 ± 8	3104 ± 148	601 ± 11	19.6	3.8
	(4′-Fluorococaine)^[3]	F	-	-	-	-	-
	(para-Isothiocyanatobenzoylecgonine methyl ester)^[4] (p-Isococ)	NCS	-	-	-	-	-

para-substituted benzoylmethylecgonines

183a

183b

183c

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183d

4'-Fluorococaine

P-ISOCOC

x170px

The MAT binding pocket analogous to the lipophilic place on cocaine-like compounds, inclusive of the benzene ring, is approximate to 9 Å in length. Which is only slightly larger than a phenyl ring by itself.^{[lower-alpha 6]}

meta-substituted benzoylmethylecgonines

Carbon 3′-hydrogen Substitutions (benzene-3′ "*meta*" substituted benzoyloxytropanes)^{[lower-alpha 7]}
^{Data-set congruent to, and aggregate with, preceding and following tables
IC₅₀ values}
S. Singh's alphanumeric assignation (name)	3′=R	DAT [³H]WIN 35428	5-HTT [³H]Paroxetine	NET [³H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
(cocaine)	H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0

184a	I	325^ɑ	-	-	-	-
184b	OH	1183 ± 115	793 ± 33	3760 ± 589	0.7	3.2
191	OBn	-	-	-	-	-
(m-Isococ)	NCS	-	-	-	-	-

^ɑIC₅₀ value for displacement of [³H]cocaine

meta-substituted benzoylmethylecgonines

184a

184b

m-ISOCOC

C3-Benzyloxycocaine

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ortho-substituted benzoylmethylecgonines

Carbon 2′-hydrogen Substitutions (benzene-2′ "*ortho*" substituted benzoyloxytropanes)^{[lower-alpha 8]}
^{Data-set congruent to, and aggregate with, preceding and following tables
IC₅₀ values}
S. Singh's alphanumeric assignation (name)	2′=R	DAT [³H]WIN 35428	5-HTT [³H]Paroxetine	NET [³H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
Cocaine	H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0

185a	I	350^ɑ	-	-	-	-
185b	F	604 ± 67	1770 ± 309	1392 ± 173	2.9	2.3
185c (2′-Acetoxycocaine)^[5]	OAc	70 ± 1	219 ± 20	72 ± 9	3.1	1.0
185d (2′-Hydroxycocaine)^[6]	OH	25 ± 4	143 ± 21	48 ± 2	5.7	1.9

^ɑIC₅₀ value for displacement of [³H]cocaine

ortho-substituted benzoylmethylecgonines

185a

185b

185c

185d

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The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.^{[lower-alpha 9]}

Manifold and termination benzoyloxy phenyl-substitutions

Vanillylmethylecgonine	186b

Multi-substitutions (substitutions of substitutions; e.g. 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.

Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple benzene-2′,3′ & 4′ combined substituted benzoyloxytropanes)^{[lower-alpha 10]}
^{Data-set (excepting instanced references inside table) congruent to, and aggregate with, preceding and following tables
IC₅₀ values}
Structure	S. Singh's alphanumeric assignation (name)	ortho-2′=R	meta-3′=R	para-4′=R	DAT [³H]WIN 35428	5-HTT [³H]Paroxetine	NET [³H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	186	HO	H	I	215 ± 19	195 ± 10	1021 ± 75	0.9	4.7
	(Vanillylmethylecgonine)^[7]	H	OCH₃	OH	-	-	-	-	-

Terminating Phenyl Carbon Ring Fusions & Alterations^{[lower-alpha 11]}
^{Data-set congruent to, and aggregate with, preceding table
IC₅₀ values}
Structure	S. Singh's alphanumeric assignation (name)	C=R	DAT [³H]Cocaine (IC₅₀)
	187	1-naphthalene	742 ± 48
	188	2-naphthalene	327 ± 63

Benzoyl and carbomethoxy branch modifications

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)^[8]

Benzoylthiomethylecgonine^[9]

A sulfur in place of the oxygen at the benzoyl ester single bond results in a lower electronegativity than that of cocaine.

Cocaine reverse ester (REC)^[10]

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

C1 substitutions^[11]
K_i values for uptake inhibition obtained on HEK-293 heterologously expressed human monoamine transporter cells.^[12]
Trivial name	R (C1 moiety)	K_i (nM) @ DAT	K_i (nM) @ SERT	K_i (nM) @ NET	σ₁ affinity K_i	σ₂ affinity K_i	IC₅₀ (μM) Na+ inhibition (Vertridine-Stimulated influx of sodium channels in Neocortical neurons)^c	LogP (XLogP3 algorithm, Cheng et al., 2007)
(—)-Cocaine	H	326 ± 106	513 ± 143	358 ± 69	6.7 ± 0.3 μM^d^[13]	"significant"^[14]	6.99 ± 2.43	2.30
(—)-1-methyl-cocaine	Me	163 ± 23	435 ± 77	488 ± 101	"unappreciable"	1.13 μM	16.01 ± 1.90	2.67
(—)-1-ethyl-cocaine	Et	95.1 ± 17.0^ɑ	1,106 ± 112	598 ± 179	—	—	—	3.20
(—)-1-n-propyl-cocaine	n-Pr	871 ± 205^ɑ	2,949 ± 462^b	796 ± 195	—	—	—	3.56
(—)-1-n-pentyl-cocaine	n-C₅H₁₁	1,272 ± 199^b	1,866 ± 400^ɑ	1,596 ± 21^b	—	—	—	4.64
(—)-1-phenyl-cocaine	Ph	32.3 ± 5.7^b	974 ± 308	1,980 ± 99^b	524 nM	198 nM	0.29 ± 0.07	3.77

^ɑ, P < 0.05 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
^b, P < 0.01 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
^cLidocaine was found to have a value of 39.6 ± 2.4, the weakest of all tested.
^dSame 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_i.^[15]
Using same data-set as above table, the following compounds were found to compare as:
- CFT @ DAT = 39.2 ± 7.1 (n = 5)
- fluoxetine @ SERT = 27.3 ± 9.2 (n = 3)
- desipramine @ NET = 2.74 ± 0.59 (n = 3)

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.^[12]

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.^[12]

cf. hydroxytropacocaine for a natural alkaloid (lacking however, the 2-position carbmethoxy) that is a C1 substituent with a hydroxy group.

2β-substitutions

Direct 2β Substitutions^{[lower-alpha 12]}
^{(IC₅₀ nM values)}
S. Singh's alphanumeric assignation (name)	R	DAT [³H]WIN 35428	5-HTT [³H]Paroxetine	NET [³H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT

(Cocaine)	Me	89 ± 4.8	1045 ± 89	3298 ± 293	11.7	37.0
196a (Cocaethylene)	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	cinnamyl	371 ± 15	368 ± 6.3	68931 ± 3476	1.0	186
196i	p-NO₂-β-phenethyl	601 ± 28	-	-	-	-
196j	p-Cl-β-phenethyl	271 ± 12	-	-	-	-
196k	p-NH₂-β-phenethyl	72 ± 7	-	-	-	-
196l	p-NCS-β-phenethyl	196 ± 14	-	-	-	-
196m	p-azido-β-phenethyl	227 ± 19	-	-	-	-
196n	(p-NHCOCH₂Br)β-phenethyl	61 ± 6	-	-	-	-
196o	(p-NHCO(CH₂)₂CO₂Et)β-phenethyl	86 ± 4	-	-	-	-
197a	NH₂	753 ± 41.3	13725 ± 1256	3981 ± 229	18.2	5.3
197b	-NMe₂	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 (Benzoylecgonine)	-OH	195000	-	-	-	-
197f	HOCH₂-	561 ± 149	-	-	-	-
197g (Tropacocaine)	H	5180 ± 1160	-	-	-	-

2β-Substituted Analogue Structures

196a (Cocaethylene)

196b

196c

196d

196e

x145px

196f

196g

196h

196i

196j

x165px

196k

196l

196m

196n

196o

x165px

197a

197b

197c

197d

197e

x145px

197f

197g

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.^{[lower-alpha 13]} Whereas 197c (Weinreb amide, N-methoxy-N-methyl amide) had a 469× increase at SERT, with greater affinity for DAT than cocaine and an equal NET affinity.^{[lower-alpha 14]} 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 dopaminergic than cocaine.^{[lower-alpha 15]} 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^{[lower-alpha 16]} appears to be unfounded.^{[lower-alpha 17]}

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 zwitterion 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 blood–brain barrier penetration than formation of a zwitterion.^{[lower-alpha 18]}

Bioisostere 2-position carbmethoxy-ester functional replacements

2β-isoxazole and isoxazoline ring containing analogues^{[lower-alpha 19]}^{[lower-alpha 20]}^{[lower-alpha 21]}
^{IC₅₀ nM values}
S. Singh's alphanumeric assignation (name)	R	[³H]Mazindol	[³H]DA	Selectivity Uptake/Binding
(Cocaine)	(H)	580 ± 70	570 ± 180	1.0

198a	H	520 ± 40	260 ± 70	0.5
198b	CO₂Et (5′-carboethoxy-)	120 ± 10	290 ± 40	2.4
198c	BOC	2230 ± 220	1820 ± 810	0.8
198d	Ph	2000 ± 640	2920 ± 1620	1.5
198e	CH=CHCO₂Me	3600 ± 400	3590 ± 1180	1.0

199a	β(or R)CO₂Et	710 ± 150	1060 ± 340	1.5
199b	α(or S)CO₂Et	5830 ± 630	8460 ± 620	1.4
200		880 ± 350	400 ± 140	0.4

2β-isoxazole and isoxazoline ring containing analogues

198a

198b

198c

198d

x165px

198e

199a

199b

200

x165px

Vinylogous 2β-position carbmethoxy-ester functional replacements

vinylogous 2β analogues^{[lower-alpha 22]}
^{Data-set congruent to, and aggregate with, preceding table
IC₅₀ nM values}
S. Singh's alphanumeric assignation	R	[³H]Mazindol	[³H]DA	Selectivity Uptake/Binding

Cocaine		580 ± 70	570 ± 180	1
201a	H	1730 ± 550	1120 ± 390	0.6
201b	Cl	222 ± 49	368 ± 190	1.6
201c	CO₂Et	50 ± 10	130 ± 10	2.6
201d	CH=CHCO₂Et	1220 ± 100	870 ± 50	0.7
201e	PO(OEt)₂	4850 ± 470	5500 ± 70	1.1

Vinylogous 2β analogues

201a

201b

201c

201d

201e

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 2β position is not absolutely necessary for the creation of high affinity cocaine analogues.^{[lower-alpha 23]}

Miscellaneous 2β-substituted cocaine analogues

[²H₅-phenyl]-cocaine

HPBE

[²H₃-N-methyl]-cocaine

C2-ethyl-OSO₂CF₂
cocaine

2-[(2-methoxy-2-oxoethoxy)methyl]
cocaine

N-modifications

Nitrogen Substitutions
Mazindol comparison table
(^ɑβ-CFT comparison notation)^{[lower-alpha 24]}
S. Singh's alphanumeric assignation (name)	N8-R	[³H]Mazindol binding	[³H]DA uptake	Selectivity Uptake/Binding
217 (Cocaine methiodide)	-	10700 ± 1530^ɑ	-	-
(Cocaine)	CH₃	280 ± 60 102^ɑ	320 ± 10	1.1
218 (Norcocaine)	H	303 ± 59^ɑ	-	-
219a	Bn	668 ± 67^ɑ	-	-
219b	Ac	3370 ± 1080^ɑ	-	-
219c	CH₂CH₂OH	700 ± 100	1600 ± 200	2.3
219d	CH₂CO₂CH₃	480 ± 40	1600 ± 100	3.3
219e	CH₂CO₂H	380 ± 20	2100 ± 400	5.5
220a	SO₂CH₃ (Ms)	1290 ± 80	1970 ± 70	1.5
220b	SO₂CF₃ (Tf)	330 ± 30	760 ± 20	2.3
220c	SO₂NCO	120 ± 10	160 ± 10	1.3
220d	SO₂Ph	20800 ± 3500	61000	2.9
220e	SO₂C₆H₄-4-NO₂ (nosyl)	5720 ± 1140	18800 ± 90	3.3
220f	SO₂C₆H₄-4-OCH₃	6820 ± 580	16400 ± 1400	2.4
221a	NO	99500 ± 12300	231700 ± 39500	2.3
221b	NO₂	7500 ± 900	21200 ± 600	2.8
221c	NHCOCH₃	>1000000	>1000000	-
221d	NH₂	-	-	-

^ɑIC₅₀ (nM) for displacement of [³H]WIN 35428

N-Modified Analogue Structures

Norcocaine (218)

219a

219b

219c

x140px

219d

219e

220a

220b

x140px

220c

220d

220e

220f

x140px

221a

221b

221c

221d

x140px

Miscellaneous N-modified cocaine analogues

N6 Regioisomer^[16]

N7 Regioisomer^[16]

ortho-Phenyl N7 Regioisomer^[16]

8-Oxa cocaine^[17]
(cf Meltzer with PTs)

x140px

Tricyclic cocaine analogues

8 to 2 tethered analogues

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes *K_i* (nM) ^{[lower-alpha 25]}
Compound (S. Singh's #)	[³H]Mazindol binding	[³H]DA uptake	[³H]5-HT uptake	[³H]NE uptake	selectivity [³H]5-HT/[³H]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	61.7 ± 8.5	60.3 ± 0.4	2.32 ± 0.23	2.69 ± 0.12	0.04
129	6.86 ± 0.43	24.0 ± 1.3	1.77 ± 0.04	1.06 ± 0.03	0.07
130a	17.2 ± 1.13	10.2 ± 1.4	78.9 ± 0.9	15.0 ± 0.4	7.8
131a	4.00 ± 0.07	2.23 ± 0.12	14.0 ± 0.6	2.99 ± 0.17	6.3
131b	3.61 ± 0.43	11.3 ± 1.1	25.7 ± 4.3	4.43 ± 0.01	2.3
132a	13.7 ± 0.8	14.2 ± 0.1	618 ± 87	3.84 ± 0.35	43.5
133a	149 ± 6	149 ± 2	810 ± 80	51.7 ± 12	5.4

See N-front & back bridged phenyltropanes.

Derivations upon fusions of the tropane's nitrogen bridge^{[lower-alpha 26]}
Compound	S. Singh's alphanumeric assignation	[³H]Mazindol	[³H]DA	Selectivity Uptake/Binding
	222	44900 ± 6200	115000 ± 15700	2.6

Back-bridged cocaine analogues are considered more akin to untethered cocaine analogs & phenyltropane derivatives (where the nitrogen 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.^{[lower-alpha 27]}

8 to 3 tethered analogues

Thiophene tricyclic tropane analogues^[18]
Compound	R	X	[³H]DA Uptake	[³H]5-HT Uptake	[³H]NE Uptake	5-HT/DA Selectivity	NE/DA Selectivity
Cocaine			259 ± 19.9	155 ± 0.4	108 ± 3.5	0.60	0.42

5a	H	CO₂Me	268 ± 16.6	2046 ± 42	26.4 ± 1.9	7.63	0.10
5b	Me	CO₂Me	403 ± 20	179 ± 38	4.9 ± 0.2	0.44	0.01
5c	I	CO₂Me	368 ± 1.6	29 ± 1.6	5 ± 1.3	0.08	0.01
7	H	CO₂iPr	428 ± 45.7	1150 ± 1.6	52.3 ± 12.0	2.69	0.12
8	H	CH₂OH	~3000	~1000	~300	~0.33	~ 0.1
9	H	CH₂OAc	610 ± 53	1530 ± 150	283 ± 16	2.51	0.46
10	H	CH₂OCOC(CH₃)₃	1020 ± 70	168 ± 53.5	1180 ± 130	0.16	1.16
11	H	CH₂OCOPh	1750 ± 140	1.53 ± 0.19	894 ± 126	0.0009	0.51
12	H	CH₂OCO-2-naphthyl	1678 ± 124	169 ± 16	1234 ± 166	0.10	0.74
13	H	CH₂NHCOCH₃	6140 ± 50	13330 ± 3150	2430 ± 340	2.17	0.39
14	H	CH₂NHCO₂C(CH₃)₃	2300 ± 380	2360 ± 30	1700 ± 60	1.03	0.74

Conformationally constrained tricyclic tropane analogues^[19]
Compound	R	X	[³H]DA Uptake	[³H]5-HT Uptake	[³H]NE Uptake	DA/5-HT Selectivity	NE/DA Selectivity
Cocaine			423 ± 147	155 ± 0.4	108 ± 3.5	2.7	0.26

8a	4-F	CO₂Me	6620 ± 460	335 ± 45	584 ± 163	2.7	0.26
8b	4-Cl	CO₂Me	853 ± 58	34.3 ± 2.9	208 ± 111	24.8	0.24
8c	3-Cl	CO₂Me	7780 ± 1580	53.6 ± 17.2	231 ± 44	145	0.03
8d	4-Br	CO₂Me	495 ± 13	11 ± 3	178 ± 9	45	0.36
8e	4-I	CO₂Me	764 ± 11	21.9 ± 0.3	213 ± 31	34.9	0.28
8f	4-CF₃	CO₂Me	N/T	12.6 ± 0.5	1830 ± 211	N/T	N/T
8g	H	CO₂Me	481 ± 11	1140 ± 70	53 ± 16	0.42	0.11
8h	4-Me	CO₂Me	649 ± 2	15 ± 0.4	146 ± 28	43.3	0.22
8i	4-OCH₃	CO₂Me	3130 ± 160	56 ± 4	187 ± 5	55.9	0.06
8j	4-iPr	CO₂Me	N/T	10.2 ± 0.4	1110 ± 200	N/T	N/T
8k	3,4-Cl₂	CO₂Me	1920 ± 260	20 ± 1	1000 ± 280	96	0.52
8l	2,3-Cl₂	CO₂Me	950 ± 107	354 ± 188	1210 ± 358	2.4	1.42
8m	3,5-Cl₂	CO₂Me	5600 ± 400	437 ± 0.3	4100 ± 500	12.8	0.73
8n	3,4-F₂	CO₂Me	7440 ± 19	101 ± 8.7	394 ± 98	73.7	0.05
8o	4-Br-3-Cl	CO₂Me	5420 ± 940	2.3 ± 0.1	459 ± 80	2360	0.08
8p	3-Cl-4-I	CO₂Me	3140 ± 450	1.8 ± 0.3	272 ± 55	1740	0.09
8q	2-Cl-4-I	CO₂Me	6640 ± 2080	74 ± 12.2	508 ± 21	89.7	0.08
8r	3-Cl-4-Me	CO₂Me	>10000	6.4 ± 1.3	198 ± 10	>1560	<0.02
8s	3,4-Me₂	CO₂Me	N/T	10.1 ± 1.1	659 ± 128	N/T	N/T

8t	1-Naphthyl	CO₂Me	9720 ± 700	121 ± 3	5370 ± 580	80.3	0.55
8u	2-Naphthyl	CO₂Me	735 ± 235	21 ± 9.9	157 ± 13	35	0.21
8v	1-Pyrenyl	CO₂Me	9920 ± 906	860 ± 20.6	N/T	11.5	N/T
8w	9-Phenanthryl	CO₂Me	1640 ± 30	233 ± 44	13000 ± 1300	39.2	0.86

"N/T" = "not tested"

Tropane ring contraction (azabornane) analogues

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).

7-Azabicyclo[2.2.1]heptane Derivatives^{[lower-alpha 28]}
Structure	S. Singh's alphanumeric assignation (name)	DAT [³H]WIN 35428 K_i (nM)
	(Cocaine)	89 ± 4.8
	155a	60400 ± 4800
	155b	96500 ± 42
	155c	5620 ± 390
	155d	18900 ± 1700

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

Phenylsulfanyl, C2-C3 unsaturated nonisomeric (C2 inclusive) C4 chloro analog.^[16]

Substitutions upon the 6 & 7 positions of the tropane^{[lower-alpha 29]}
S. Singh's alphanumeric assignation (name)	X	K_i (nM) [³H]Mazindol binding	K_i (nM) [³H]DA uptake	Selectivity Uptake/Binding
(Cocaine)		280 ± 60	320 ± 10	1.1
(Pseudococaine)		10400 ± 300	13800 ± 1500	1.3
225a	2β, 6β-OCH₃	98000 ± 12000	68000 ± 5000	0.7
225b	2α, 6β-OCH₃	190000 ± 11000	510000 ± 110000	2.7
225c	2β, 7β-OCH₃	4200 ± 100	6100 ± 200	1.4
225d	2α, 7β-OCH₃	45000 ± 5000	110000 ± 4000	2.4
225e	2α, 7α-OCH₃	54000 ± 3000	200000 ± 70000	3.7

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

4′-Iodococaine-2β-substituted analogues^{[lower-alpha 30]}
S. Singh's alphanumeric assignation	2β-R	C2′-R	IC₅₀ (nM) (displacement of [³H]WIN 35428)

211a	CO₂OH	H	6214 ± 1269
211b	CH₂OCOCH₃	H	2995 ± 223
211c	CONHCH₃	H	>100000
211d	CO₂Et	H	2031 ± 190
211e	CO₂-i-Pr	H	1377 ± 10
211f	CO₂Ph	H	2019 ± 253
211g	CO₂CH₂Ph	H	4602 ± 325
211h	3-phenyl-1,2,4-oxadiazole	H	3459 ± 60
211i	CH=CH₂	H	2165 ± 253
211j	CH₂CH₃	H	2692 ± 486
212	CO₂-i-Pr	HO	663 ± 70 4507 ± 13^ɑ 34838 ± 796^b

^ɑFor displacement of [³H]paroxetine (5-HTT & NET)
^bFor displacement of [³H]nisoxetine (5-HTT & NET)

4′-Iodococaine-2β-substituted analogues

211a

211b

211c

211d

211e

200px

211f

211g

211h

211i

211j

200px

3β-Carbamoyl analogues

3-position carbamoyl linkage substituting benzoyloxy analogues^{[lower-alpha 31]}
S. Singh's alphanumeric assignation (name)	X	IC₅₀ (nM) inhibition of [³H]Cocaine binding (Rat Striatal Tissue)	IC₅₀ (nM) inhibition of [³H]DA uptake (Rat Striatal Tissue)	Selectivity uptake/binding
(Cocaine)	(H)	70 ± 10	210 ± 70	3.0

223a	H	5600 ± 700	52600 ± 3000	9.4
223b	4-NO₂	1090 ± 250	5700 ± 1200	5.2
223c	4-NH₂	63300 ± 12200	>100000	-
223d	4-N₃	1000 ± 240	1180 ± 360	1.2
223e	4-NCS	260 ± 60	490 ± 80	1.9

223f	3-NO₂	37 ± 10	178 ± 23	4.8
223g	3-NH₂	2070 ± 340	23100 ± 900	11.1
223h	3-N₃	630 ± 150	3900 ± 1590	6.2
223i	3-NCS	960 ± 210	4900 ± 420	5.1

3β-Carbamoyl analogues

223a

223b

223c

x160px

223d

223e

223f

x160px

223g

223h

223i

x160px

Phenyl 3-position linkage substitutions

A 3-Dimensional (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 trans to optimize its functional stimulation.)

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.

See: List of phenyltropanes (Many phenyltropanes are derived from cocaine metabolites, such as methylecgonidine, as precursors. Whereas fully synthetic methods have been devised from the starting material of vinylcarbenoids & pyrroles.)^[20]

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 of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.^{[lower-alpha 32]} This may account for PTs increased behavioral stimulation profile over cocaine.^{[lower-alpha 33]} Differences in binding potency have also been explained considering solvation effects; cocaine containing 2β,3β-ester groups being calculated as more solvated than the WIN-type compounds (i.e. troparil). Higher pK_ɑs 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.^{[lower-alpha 34]}

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.^[21] (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 action potential blockage with a molecule capable of intersecting its specific channel, in the case of cocaine a sodium channel, that potentially serves in 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 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 enacting in as readily responsive a manner to its conformational change.^[22]

Various phenyltropane examples

3β-Alkylphenyltropane & 3β-Alkenyl analogues

3-position alkylphenyl linkage substituting benzoyloxy analogues^{[lower-alpha 35]}
S. Singh's alphanumeric assignation (name)	n	IC₅₀ (nM) [³H]Cocaine binding	IC₅₀ (nM) [³H]DA uptake	Selectivity uptake/binding
(Cocaine)		101 ± 26	209 ± 20	2.1

224a	₁	885 ± 18	1020 ± 52	1.1
224b	₂	9.9 ± 0.33	70.5 ± 1.0	7.1
224c	₃	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

3β-Alkylphenyltropane & 3β-Alkenyl analogues

224a

224b

224c

224d

224e

x120px

x140px

The compound 224e, the 3β-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.^{[lower-alpha 36]}

6-Alkyl-3-benzyltropane analogues

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues^{[lower-alpha 37]}
Sub-category (S. Singh compound #)	b R=Me	c R=Et	d R=n-Pr	e R=n-Bu
2β,6α-isomers: (229a—f)
2β,6α-isomers: (229a—f)	x120px	x120px	x120px	x120px
2α,6α-isomers: (230a—f)
2α,6α-isomers: (230a—f)	x110px	x110px	x120px	x120px
2β,6β-isomers: (231a—f)
2β,6β-isomers: (231a—f)	x110px	x110px	x100px	x100px
2α,6β-isomers: (232a—f)
2α,6β-isomers: (232a—f)	x110px	x110px	x100px	x90px

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues^{[lower-alpha 38]}
S. Singh's alphanumeric assignation (name/WIN number)	R	K_i (nM) [³H]WIN 35428 binding	IC₅₀ (nM) [³H]DA uptake	Selectivity uptake/binding
Cocaine		32 ± 5 338 ± 221	405 ± 91 405 ± 91	12.6 1.2
WIN 35065-2		33 ± 17 314 ± 222	373 ± 10	11.3

(−)-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	-	-

(+)-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	-	-

231b	Me	57 ± 5	107 ± 36	1.9
231c	Et	3110 ± 187	-	-
231d	n-Pr	5850 ± 702	-	-
231f	Bn	1560 ± 63	-	-

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	-	-

Benzylidene derivatives of 6-alkyl-3-benzyltropanes^{[lower-alpha 39]}
Sub-category (S. Singh compound #)	b R=Me	c R=Et	d R=n-Pr	e R=n-Bu
6α-isomers: (237a—f)
6α-isomers: (237a—f)	x105px	x110px	x125px	x135px
6β-isomers (exo): (238a—f)
6β-isomers (exo): (238a—f)	x85px	x85px	x85px
3β-benzyl derivatives: (239a—f)
3β-benzyl derivatives: (239a—f)	x110px	x110px	x130px	x135px
intermediate alkylidene esters: (240a—f)
intermediate alkylidene esters: (240a—f)	x115px	x115px	x130px	x135px

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

above: Strobamine, a DARI functional cocaine analog with structural semblance.^[23] Compare the phenyltropane length tropane C2 & C3 functional group fusion variant.^[24]

below: Chalcostrobamine

cf. strobamine (at right) for a more efficacious compound as like the below.

2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.^[25]
(Binding values @ biogenic amine transporters (BATs) for rigid and semi-rigid analogs)
alphanumeric assignation	R₁	R₂	hDAT IC₅₀ (nM)	hSERT IC₅₀ (nM)	hNET IC₅₀ (nM)

(—)-3a	H	C₆H₅	58,300 (20,200)	6140 (3350)	NA
(+)-3a	H	C₆H₅	48,700 (20,100)	6030 (3400)	NA

(—)-3b	H	NH₂	NA	NA	NA
(+)-3b	H	NH₂	NA	NA	NA

(—)-3c	H	CH₃	NA	NA	NA
(+)-3c	H	CH₃	NA	NA	NA

(—)-3d	H	H	NA	NA	NA
(+)-3d	H	H	NA	NA	NA
(+/—)-3e	C₆H₅	C₆H₅	30,000 (11,200)	3650 (1700)	NA

"NA" = "no affinity", e.g. unquantifiable.

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.^[25]

Piperidine cocaine-homologues

Tricyclo benzoyloxy dibenzene cocaine analogue. cf. benztropine compound #277, tropatepine, etc.^[16]

Binding potency of piperidine homologues for displacement of [³H]WIN 35428^{[lower-alpha 40]}
S. Singh's alphanumeric assignation (name)	2β-R	IC₅₀ (nM)
(Cocaine)	CO₂CH₃ (i.e. CO₂Me)	249 ± 37
183a	CO₂CH₃	2522 ± 4
242	H	11589 ± 4
243	CO₂CH₃	8064 ± 4

cf. phenyltropane piperidine-homologues for compounds with a more optimized conformation that yield higher affinities when binding to MAT.

Cocaine hapten analogues

"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.^[26]

Cocaine analogs which elicit noncatalytic antibodies^{[lower-alpha 41]}
Compound	S. Singh's alphanumeric assignation (name)	2β-R
	394 (GNC)^ɑ	CO₂(CH₂)₅CO₂H
	395 (Succinyl Norcocaine)^[27]	CO₂CH₃
	GNE^b^[28] including carrier proteins: GNE-FLiC GNE-KLH GNE-BSA
	396	CONH(CH₂)₅CO₂H

^ɑ6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carbonyloxy-hexanoic acid
^b6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid

Tetrahedral-intermediate cocaine-hapten compound #400

Cocaine transition state analogues (TSAs) which generate catalytic antibodies^{[lower-alpha 42]}
Compound	S. Singh's alphanumeric assignation (name)	R

	401a	CH₃
	401b	(CH₂)₅CO₂H
	401c	CH₂CO₂H
	401d	COCH₂CH₂CO₂H
	401e	H
	401f	CH₂CH₂Br
	385g	(CH₂)₂NHCO(CH₂)₂CONH₂

	402a	O(CH₂)₄NHCO(CH₂)₂CO₂N(CO₂)₂C₆H₄
	402b	OH
	402c	O(CH₂)₂(p-NH₂C₆H₄)
	402d	NH(CH₂)₅CO₂H
	402e	O(CH₂)₄NHCO(CH₂)₂CONH₂

	403a	NH₂
	403b	NHCOCH₂Br
	403c	NHCO(CH₂)₃CO₂H
	403d	(CH₂)₃NHCO(CH₂)₂CONH₂

Cocaine haptens that create catalytic anti-bodies require transitional states as affected in vivo. Monoclonal antibodies generated against BSA-coupled 402e accelerated the rate of cocaine hydrolysis by ~23,000x and eliminated the reinforcing effects of cocaine administration in rats.^[29]^[30]^[31]^[32]

Anti-idiotypic & butyl-cholinesterase mediated immunopharmacotherapy cocaine analogs^[33]
K1-KLH/BSA^[34]	K2-KLH/BSA

Structural/Functional intermediate analogues

Piperidine Analogues

JZ-IV-10 (a "Modafinil hybrid" with nocaine.^[35] cf. List of modafinil analogues)

Nocaine

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.^[36] 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-D-glucoside."

Benzoyl-beta-D-glucoside

Benztropine (3α-Diphenylmethoxy Tropane) Analogues

3α-Diphenylmethoxy tropanes
(Benztropine analog affinities binding to DAT & DA uptake)^{[lower-alpha 43]}
S. Singh's alphanumeric assignation (name)	R	R′	K_i (nM) [³H]WIN 35428 binding	IC₅₀ (nM) [³H]DA uptake	Selectivity uptake/binding
(Cocaine)			388 ± 47	-	-
(GBR 12909)			11.6 ± 31	-	-

(Benztropine)	H	H	118 ± 9	403 ± 115	3.4
249a	4′-F	H	32.2 ± 10	48	1.5
249b (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′-NO₂	H	197 ± 8	219	1.1
249k	4′-CN	H	196 ± 9	222	1.1
249l	4′-CF₃	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′-CF₃	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′-NH₂	H	840 ± 8	373 ± 117	0.4

3α-Diphenylmethoxy-2β-carbomethoxybenztropine
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)^{[lower-alpha 44]}
S. Singh's alphanumeric assignation (name)	R	R′	IC₅₀ (nM) DAT (Binding of [³H]WIN 35428)	IC₅₀ (nM) 5-HTT (Binding of [³H]Citalopram)	Selectivity 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

S-257a	H	H	33.5 ± 4.5	10100 ± 1740	301
S-257b	H	F	13.2 ± 1.9	4930 ± 1200	373
S-257c (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

N-Modified 2-carbomethoxybenztropines
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)^{[lower-alpha 45]}
S. Singh's alphanumeric assignation (name)	R	n	IC₅₀ (nM) DAT (Binding of [³H]WIN 35428)	IC₅₀ (nM) 5-HTT (Binding of [³H]Citalopram)	Selectivity 5-HTT/DAT

258a			20.3 ± 3.5	-	-
258b	H	₁	223 ± 53	4970 ± 700	22.3
258c	H	₃	22.0 ± 11.9	19.7 ± 3	0.9
258d	Br	₃	80.2 ± 8.8	234 ± 0.5	2.9
258e	I	₃	119 ± 11	2200 ± 1250	18.5
258f	H	₅	99.0 ± 28	550 ± 63	5.5
259			616 ± 88	55200 ± 20000	89.3

N-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes
(Benztropine affinities to DAT & 5-HTT)^{[lower-alpha 46]}
S. Singh's alphanumeric assignation (name)	R	K_i (nM) DAT (Binding of [³H]WIN 35428)	IC₅₀ (nM) 5-HTT (Uptake of [³H]DA)	Selectivity uptake/binding

260 (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%^ɑ	-	-
265b	mesyl	18%^ɑ	-	-
(AHN 2-005)^[37]	CH₂CH=CH₂	-	-	-
(JHW 007)^[37]	CH₂CH₂CH₂CH₃	-	-	-
(GA 2-99)^[37]	CH₂CH₂NH₂	-	-	-
(GA 103)^[37]	CH₂CH₂CH₂CH₂Ph	-	-	-
266		108 ± 12	130	1.2

^ɑInhibition at 10 μM

8-Oxa-2-carbomethoxy norbenztropines
(8-Oxanortropane benztropine analog affinities to DAT & 5-HTT)^{[lower-alpha 47]}
S. Singh's alphanumeric assignation (name)		IC₅₀ (nM) DAT (Binding of [³H]WIN 35428)	IC₅₀ (nM) 5-HTT (Binding of [³H]Citalopram)
R/S-268	2β,3β	>10000	>1660
R/S-269	2α,3β	20300	>1660
R/S-270	2α,3α	22300	>1660
R/S-271	2β,3α	520	>1660

3α-Diphenylmethoxytropane Analogues of Cocaine

Benzatropine

Etybenzatropine

Difluoropine (O-620)

PG01053

276

277

Etybenzatropine

Difluoropine is a stimulant drug which acts as a more selective dopamine reuptake inhibitor than cocaine.

PG01053

Compound 276

MFZ 4-86

MFZ 2-71

3-CPMT

JHW 007-d9^[38]

GA 103

AHN 1-055

x165px

3-CPMT

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)

N-phenylpropyl bis-4-fluorobenztropine.

The binding of benztropine analogues to the 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. ^[39] 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.^[40]^[41]

Tropanyl Isoxazoline Analogues

Tropanyl-Δ²-isoxazoline derivatives^[42]

4a

4c

5a

5c

x210px

x190px

6a

6b

6c

7a

x170px

7b

7c

8a

8b

x190px

8c

9a

9b

9c

x170px

10a

10b

10c

11a

x170px

x190px

11b

12a

12b

x180px

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.

7a is the only known compound to allosterically modulate SERT in such a way within in vitro conditions (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_max with small change in the Km 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 ibogaine (save for the function by which its anti-addictive properties are thought to be mediated, i.e. α₃β₄ nicotinic channel blockage. cf. 18-Methoxycornaridine for such nicotinergic activity without the likewise SERT affinity).^[43]

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

EXP-561	Butyltolylquinuclidine

Dihydroimidazoles

Possible substitutions of the Mazindol molecular structure.

See: List of Mazindol analogues

Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for e.g. Beagles^{[lower-alpha 48]}) 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 N-Ethylmaleimide being able to inhibit approximately 95% of the specific binding of [³H]Mazindol to the residues of the MAT binding site(s), however said effect of 10 mM N-Ethylmaleimide was prevented in its entirety by just 10 μM cocaine. Whereas neither 300 μM dopamine or D-amphetamine afforded sufficient protection to contrast the efficacy of cocaine.^{[lower-alpha 49]}

Local anesthetics (not usually CNS stimulants)

Amylocaine, or Stovaine (above), the first synthetically constructed local anesthetic. Compare structure to dimethylaminopivalophenone (below), an analgesic (opioid). Cocaine's classification as a narcotic under 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.^[44]

In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,^[45] 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.^[45] 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.

List of local anesthetics
Name	Other common names
Amylocaine	Stovaine
Articaine	Astracaine, Carticaine, Septanest, Septocaine, Ultracaine, Zorcaine
Benzocaine	Anbesol, Lanacane, Orajel
Bupivacaine	Marcaine, Sensorcaine, Vivacaine
Butacaine	Butyn
Chloroprocaine	Nesacaine
Cinchocaine/Dibucaine	Cincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
Cyclomethycaine	Surfacaine, Topocaine
Etidocaine	Duranest
Eucaine	α-eucaine, β-eucaine
Fotocaine^[46]
Hexylcaine	Cyclaine, Osmocaine
Levobupivacaine	Chirocaine
Lidocaine/Lignocaine	Xylocaine, Betacaine
Mepivacaine	Carbocaine, Polocaine
Meprylcaine/Oracaine	Epirocain
Metabutoxycaine	Primacaine
Phenacaine/Holocaine	Holocaine
Piperocaine	Metycaine
Pramocaine/Pramoxine	Pramoxine
Prilocaine	Citanest
Propoxycaine/Ravocaine	Pravocaine, Ranocaine, Blockain
Procaine/Novocaine	Borocaine (Procaine Borate), Ethocaine
Proparacaine/Alcaine	Alcaine
Quinisocaine	Dimethisoquin
Risocaine	Propaesin, Propazyl, Propylcain
Ropivacaine	Naropin
Tetracaine/Amethocaine	Pontocaine, Dicaine
Trimecaine	Mesdicain, Mesocain, Mesokain

Notes (inclu. specific locations of citations from within references used)

↑ ^[1] ←Page #969 (45th page of article) §III. ¶1. Final line. Last sentence.
↑ ^[1] ←Page #1,018 (94th page of article) 2nd column, 2nd paragraph.
↑ ^[1] ←Page #940 (16th page of article) underneath Table 8., above §4
↑ ^[1] ←Page #970 (46th page of article) Table 27. Figure 29.
↑ ^[1] ←Page #971 (47th page of article) Figure 30. & Page #973 (49th page of article) Table 28.
↑ ^[1] ←Page #982 (58th page of article)
↑ ^[1] ←Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
↑ ^[1] ←Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
↑ ^[1] ←Page #972 (48th page of article) ¶2, Line 10.
↑ ^[1] ←Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
↑ ^[1] ←Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
↑ ^[1] ←Page #973 (49th page of article) §C. & Page #974 (50th page of article) Figure 31 & Page #976 (52nd page of article) Table 29.
↑ ^[1] ←Page #974 (50th page of article) Final ¶ (5th), Second line.
↑ ^[1] ←Page #975 (51st page of article) First ¶, first line.
↑ ^[1] ←Page #975 (51st page of article) First ¶, 4th line.
↑ ^[1] ←Page #974 (50st page of article) First (left) column, third ¶
↑ ^[1] ←Page #937 (13th page of article) Second (right) column, first ¶. Above/before §2
↑ ^[1] ←Page #974 (50st page of article) First (left) column, fourth ¶
↑ ^[1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
↑ ^[1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
↑ ^[1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
↑ ^[1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
↑ ^[1] ←Page #976 (52nd page of article)
↑ ^[1] ←Page #978 (54th page of article) §D & Page #980 (56th page of article) Figure 33 & Page #981 (57th page of article) Table 32.
↑ ^[1] ←Page #964 (39th page of article) Table 23.
↑ ^[1] ←Page #980 (56th page of article) Scheme 52.
↑ ^[1] ←Page #963 (39th page of article) 2nd (right side) column, 2nd paragraph.
↑ ^[1] ←Page #967 (43rd page of article) §C. & Page #967 (43rd page of article) Table 25
↑ ^[1] ←Page #982 (58th page of article) §G & Page #983 (59th page of article) Figure 36 & Page #984 (60th page of article) Table 35.
↑ ^[1] ←Page #979 (55th page of article) Table 31.
↑ ^[1] ←Page #981 (57th page of article) §E & Page #982 (58th page of article) Table 33.
↑ ^[1] ←Page #970 (46th page of article) §B, 10th line
↑ ^[1] ←Page #971 (47th page of article) 1st ¶, 10th line
↑ ^[1] ←Page #949 (25th page of article) 3rd ¶, 20th line
↑ ^[1] ←Page #982 (58th page of article) §F, Table 34 & Figure 35.
↑ ^[1] ←Page #982 (58th page of article) 3rd ¶, lines 2, 5 & 6.
↑ ^[1] ←Page #984 (60th page of article) Figure 37.
↑ ^[1] ←Page #984 (60th page of article) §H, Figure 37 & Page #985 (61st page of article) Table 36.
↑ ^[1] ←Page #984 (60th page of article) Scheme 56.
↑ ^[1] ←Page #986 (62nd page of article) §I, Table 37 & Scheme 58
↑ ^[1] ←Page #1,014 (90th page of article) §VIII, A. Figure 59.
↑ ^[1] ←Page #1,016 (92nd page of article) Figure 60.
↑ ^[1] ←Page #987 (63rd page of article) §IV, Figure 39 & Page #988 (64th page of article) Table 38.
↑ ^[1] ←Page #987 (63rd page of article) Figure 40, Page #988 (64th page of article) §B & Page #989 (65th page of article) Table 39.
↑ ^[1] ←Page #987 (63rd page of article) Figure 41, Page #989 (65th page of article) §C & Page #990 (66th page of article) Table 40.
↑ ^[1] ←Page #988 (64th page of article) Figure 42, Page #990 (66th page of article) §2 & Page #992 (68th page of article) Table 41.
↑ ^[1] ←Page #988 (64th page of article) Figure 43, Page #992 (68th page of article) §3 & Table 42.
↑ ^[1] ←Page #1,011 (87th page of article) §VII (7) 1st ¶.
↑ ^[1] ←Page #969 (45th page of article) 2nd (right-side) column 2nd ¶.

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↑ Skeptics Stack Exchange: Is sugar one element away from cocaine (or any other drug?)
↑ ^37.0 ^37.1 ^37.2 ^37.3 Loland, C. J.; Desai, R. I.; Zou, M.-F.; Cao, J.; Grundt, P.; Gerstbrein, K.; Sitte, H. H.; Newman, A. H. et al. (2007). "Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors". Molecular Pharmacology 73 (3): 813–823. doi:10.1124/mol.107.039800. ISSN 0026-895X. PMID 17978168.
↑ Tanda, Gianluigi; Newman, Amy Hauck; Ebbs, Aaron L.; Tronci, Valeria; Green, Jennifer L.; Tallarida, Ronald J.; Katz, Jonathan L. (September 2009). "Combinations of Cocaine with Other Dopamine Uptake Inhibitors: Assessment of Additivity". Journal of Pharmacology and Experimental Therapeutics 330 (3): 802–809. doi:10.1124/jpet.109.154302. PMID 19483071.
↑ Schmitt, KC; Rothman, RB; Reith, ME (2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". J. Pharmacol. Exp. Ther. 346 (1): 2–10. doi:10.1124/jpet.111.191056. PMID 23568856.
↑ Rothman, RB; Baumann, MH; Prisinzano, TE; Newman, AH (2008). "Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction". Biochem Pharmacol 75 (1): 2–16. doi:10.1016/j.bcp.2007.08.007. PMID 17897630.
↑ Runyon, SP; Carroll, FI (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Curr Top Med Chem 6 (17): 1825–43. doi:10.2174/156802606778249775. PMID 17017960.
↑ C. Dallanoce et al. - Bioorg. Med. Chem. 20 (2012) 6344-6355
↑ Dallanoce, Clelia; Canovi, Mara; Matera, Carlo; Mennini, Tiziana; De Amici, Marco; Gobbi, Marco; De Micheli, Carlo (2012). "A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake". Bioorganic & Medicinal Chemistry 20 (21): 6344–6355. doi:10.1016/j.bmc.2012.09.004. ISSN 0968-0896. PMID 23022052.
↑ Ruetsch, YA; Böni, T; Borgeat, A (Aug 2001). "From cocaine to ropivacaine: the history of local anesthetic drugs". Curr Top Med Chem 1 (3): 175–82. doi:10.2174/1568026013395335. PMID 11895133.
↑ ^45.0 ^45.1 Wilcox, K.M.; Kimmel, H.L.; Lindsey, K.P.; Votaw, J.R.; Goodman, M.M.; Howell, L.L. (2005). "In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys". Synapse 58 (4): 220–228. doi:10.1002/syn.20199. PMID 16206183. http://research.yerkes.emory.edu/Howell/Synapse58.pdf.
↑ Cite error: Invalid <ref> tag; no text was provided for refs named SchoenbergerDamijonaitis2014
↑ U.S. Patent 6,479,509 Patent inventor Frank Ivy Carroll, Assignee: Research Triangle Institute
↑ U.S. patent US6479509 B1 structures given for submission, 5th compound down in image.

External links

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Original source: https://en.wikipedia.org/wiki/List of cocaine analogues. Read more

[2] [1] ←Page #969 (45th page of article) §III. ¶1. Final line. Last sentence.

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[Singh2-1] 1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 ^1.11 ^1.12 ^1.13 ^1.14 ^1.15 ^1.16 ^1.17 ^1.18 ^1.19 ^1.20 ^1.21 ^1.22 ^1.23 ^1.24 ^1.25 ^1.26 ^1.27 ^1.28 ^1.29 ^1.30 ^1.31 ^1.32 ^1.33 ^1.34 ^1.35 ^1.36 ^1.37 ^1.38 ^1.39 ^1.40 ^1.41 ^1.42 ^1.43 ^1.44 ^1.45 ^1.46 ^1.47 ^1.48 Singh, Satendra (2000). "Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists". Chem. Rev. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256. https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf.

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[9] Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. (1992). "Cocaine Receptor: Biochemical Characterization and Structure-Activity Relationships of Cocaine Analogues at Dopamine Transporter". Journal of Medicinal Chemistry 35 (6): 969–981. doi:10.1021/jm00084a001. PMID 1552510.

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[Vanillyl-17] Smith, RM; Poquette, MA; Smith, PJ (1984). "Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine". Journal of Analytical Toxicology 8 (1): 29–34. doi:10.1093/jat/8.1.29. PMID 6708474.

[19] Sakamuri, Sukumar (2000). "Synthesis of novel spirocyclic cocaine analogs using the Suzuki coupling". Tetrahedron Letters 41 (13): 2055–2058. doi:10.1016/S0040-4039(00)00113-1.

[20] Isomura, Shigeki; Hoffman, Timothy Z.; Wirsching, Peter; Janda, Kim D. (2002). "Benzoylthio-. cocaine, analogue substitution. Synthesis, Properties, and Reactivity of Cocaine Benzoylthio Ester Possessing the Cocaine Absolute Configuration". J. Am. Chem. Soc. 124 (14): 3661–3668. doi:10.1021/ja012376y. PMID 11929256.

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[DavisGaddiraju2012-22] Davis, Franklin A.; Gaddiraju, Narendra V.; Theddu, Naresh; Hummel, Joshua R.; Kondaveeti, Sandeep K.; Zdilla, Michael J. (2012). "Enantioselective Synthesis of Cocaine C-1 Analogues using Sulfinimines (N-Sulfinyl Imines)". The Journal of Organic Chemistry 77 (5): 2345–2359. doi:10.1021/jo202652f. ISSN 0022-3263. PMID 22300308. https://figshare.com/articles/Enantioselective_Synthesis_of_Cocaine_C_1_Analogues_using_Sulfinimines_i_N_i_Sulfinyl_Imines_/2544925.

[ReithAli2012-23] 12.0 ^12.1 ^12.2 Reith, M. E. A.; Ali, S.; Hashim, A.; Sheikh, I. S.; Theddu, N.; Gaddiraju, N. V.; Mehrotra, S.; Schmitt, K. C. et al. (2012). "Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine". Journal of Pharmacology and Experimental Therapeutics 343 (2): 413–425. doi:10.1124/jpet.112.193771. ISSN 1521-0103. PMID 22895898. Full article

[24] Sharkey, J; Glen, KA; Wolfe, S; Kuhar, MJ (1988). "Cocaine binding at sigma receptors". Eur J Pharmacol 149 (1–2): 171–4. doi:10.1016/0014-2999(88)90058-1. PMID 2840298.

[NuwayhidWerling2006-25] Nuwayhid, Samer J.; Werling, Linda L. (2006). "Sigma2 (σ2) receptors as a target for cocaine action in the rat striatum". European Journal of Pharmacology 535 (1–3): 98–103. doi:10.1016/j.ejphar.2005.12.077. ISSN 0014-2999. PMID 16480713.

[26] Involvement of the Sigma₁ 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

[Carroll-40] 16.0 ^16.1 ^16.2 ^16.3 ^16.4 U.S. Patent 6,479,509

[41] Kozikowski, A. P.; Simoni, D.; Roberti, M.; Rondanin, R.; Wang, S.; Du, P.; Johnson, K. M. (1999). "Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity". Bioorganic & Medicinal Chemistry Letters 9 (13): 1831–1836. doi:10.1016/S0960-894X(99)00273-5. PMID 10406650.

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[46] Zhang, Ao; Zhou, Guochun; Hoepping, Alexander; Mukhopadhyaya, Jayanta; Johnson, Kenneth M.; Zhang, Mei; Kozikowski, Alan P. (April 2002). "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 of Medicinal Chemistry 45 (9): 1930–1941. doi:10.1021/jm0105373. PMID 11960503.

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[56] Sahlholm, Kristoffer; Nilsson, Johanna; Marcellino, Daniel; Fuxe, Kjell; Århem, Peter (2012). "Voltage sensitivities and deactivation kinetics of histamine H₃ and H₄ receptors". Biochimica et Biophysica Acta (BBA) - Biomembranes 1818 (12): 3081–3089. doi:10.1016/j.bbamem.2012.07.027. PMID 22885137. ...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...

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[78] Skeptics Stack Exchange: Is sugar one element away from cocaine (or any other drug?)

[LolandDesai2007-83] 37.0 ^37.1 ^37.2 ^37.3 Loland, C. J.; Desai, R. I.; Zou, M.-F.; Cao, J.; Grundt, P.; Gerstbrein, K.; Sitte, H. H.; Newman, A. H. et al. (2007). "Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors". Molecular Pharmacology 73 (3): 813–823. doi:10.1124/mol.107.039800. ISSN 0026-895X. PMID 17978168.

[85] Tanda, Gianluigi; Newman, Amy Hauck; Ebbs, Aaron L.; Tronci, Valeria; Green, Jennifer L.; Tallarida, Ronald J.; Katz, Jonathan L. (September 2009). "Combinations of Cocaine with Other Dopamine Uptake Inhibitors: Assessment of Additivity". Journal of Pharmacology and Experimental Therapeutics 330 (3): 802–809. doi:10.1124/jpet.109.154302. PMID 19483071.

[86] Schmitt, KC; Rothman, RB; Reith, ME (2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". J. Pharmacol. Exp. Ther. 346 (1): 2–10. doi:10.1124/jpet.111.191056. PMID 23568856.

[Rothman-87] Rothman, RB; Baumann, MH; Prisinzano, TE; Newman, AH (2008). "Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction". Biochem Pharmacol 75 (1): 2–16. doi:10.1016/j.bcp.2007.08.007. PMID 17897630.

[Runyon-88] Runyon, SP; Carroll, FI (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Curr Top Med Chem 6 (17): 1825–43. doi:10.2174/156802606778249775. PMID 17017960.

[89] C. Dallanoce et al. - Bioorg. Med. Chem. 20 (2012) 6344-6355

[DallanoceCanovi2012-90] Dallanoce, Clelia; Canovi, Mara; Matera, Carlo; Mennini, Tiziana; De Amici, Marco; Gobbi, Marco; De Micheli, Carlo (2012). "A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake". Bioorganic & Medicinal Chemistry 20 (21): 6344–6355. doi:10.1016/j.bmc.2012.09.004. ISSN 0968-0896. PMID 23022052.

[93] Ruetsch, YA; Böni, T; Borgeat, A (Aug 2001). "From cocaine to ropivacaine: the history of local anesthetic drugs". Curr Top Med Chem 1 (3): 175–82. doi:10.2174/1568026013395335. PMID 11895133.

[Wilcox-94] 45.0 ^45.1 Wilcox, K.M.; Kimmel, H.L.; Lindsey, K.P.; Votaw, J.R.; Goodman, M.M.; Howell, L.L. (2005). "In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys". Synapse 58 (4): 220–228. doi:10.1002/syn.20199. PMID 16206183. http://research.yerkes.emory.edu/Howell/Synapse58.pdf.

[SchoenbergerDamijonaitis2014-95] Cite error: Invalid <ref> tag; no text was provided for refs named SchoenbergerDamijonaitis2014

[96] U.S. Patent 6,479,509 Patent inventor Frank Ivy Carroll, Assignee: Research Triangle Institute

[97] U.S. patent US6479509 B1 structures given for submission, 5th compound down in image.

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[1]

v t e Phenyltropanes (classifications)
2-Carboxymethyl Esters	Troparil WIN 35428 RTI-31 RTI-32 RTI-51 RTI-55 RTI-83
(3,4-Disubstituted Phenyl)-tropanes	Dichloropane RTI-112 RTI-353
Arylcarboxy	RTI-113 RTI-120
Carboxyalkyl	RTI-121 RTI-150
Acyl	PTT/WF-11 WF-23 PIT/WF-21 WF-33
β,α Stereochemistry	RTI-352 RTI-274
α,β Stereochemistry	Brasofensine Tesofensine NS2359
Heterocycles: 3-Substituted-isoxazol-5-yl	RTI-177 RTI-336 RTI-371
Heterocycles: 3-Substituted-1,2,4-oxadiazole	RTI-126 RTI-371
N-alkyl	FP-β-CPPIT FE-β-CPPIT Altropane Ioflupane (¹²³I)
N-replaced (S,O,C)	Tropoxane
Irreversible	RTI-76
Nortropanes (N-demethylated)	NS2359 (GSK-372,475)

v t e Stimulants
Adamantanes	Adapromine Amantadine Bromantane Memantine Rimantadine
Adenosine antagonists	8-Chlorotheophylline 8-Cyclopentyltheophylline 8-Phenyltheophylline Aminophylline Caffeine CGS-15943 Dimethazan Paraxanthine SCH-58261 Theobromine Theophylline
Alkylamines	Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Levopropylhexedrine Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane
Ampakines	CX-516 CX-546 CX-614 CX-691 CX-717 IDRA-21 LY-404,187 LY-503,430 Nooglutyl Org 26576 PEPA S-18986 Sunifiram Unifiram
Arylcyclohexylamines	Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine
Benzazepines	6-Br-APB SKF-77434 SKF-81297 SKF-82958
Cholinergics	A-84,543 A-366,833 ABT-202 ABT-418 AR-R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine PHA-543,613 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A SIB-1553A SSR-180,711 TC-1698 TC-1827 TC-2216 Tebanicline UB-165 Varenicline WAY-317,538
Convulsants	Anatoxin-a Bicuculline DMCM Flurothyl Gabazine Haldol Pentetrazol Picrotoxin Strychnine Thujone
Eugeroics	Adrafinil Armodafinil CRL-40,940 CRL-40,941 Fluorenol Modafinil
Oxazolines	4-Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone
Phenethylamines	1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fuoroamphetamine 2-Fuoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fuoroamphetamine 3-Fluoroethamphetamine 3-Fluoromethcathinone 3-Methoxyamphetamine 3-Methylamphetamine 3,4-DMMC 4-BMC 4-CMC 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-Methylbuphedrone 4-Methylcathinone 4-MEAP 4-MMA 4-Methylpentedrone 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amfepramone Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzedrone Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Buphedrone Bupropion Butylone Camfetamine Cathine Cathinone Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D-Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dimethylcathinone Dobutamine DOPA (Dextrodopa, Levodopa) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethcathinone Ethylnorepinephrine Ethylone Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Feprosidnine Flephedrone Fludorex Formetorex Furfenorex Gepefrine Hexapradol Hexedrone HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine Indanylamphetamine Iofetamine Isoetarine Isoethcathinone Isoprenaline L-Deprenyl (Selegiline) Lefetamine Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA (midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephedrone Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxamine Methoxyphenamine MMA Methcathinone Methedrone Methoxyphenamine Methylenedioxycathinone Methylone Mexedrone MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N-Ethylbuphedrone N-Ethylhexedrone N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L-Norpseudoephedrine Octopamine (drug) Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Pentedrone Pentylone Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Phthalimidopropiophenone Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol (Levosalbutamol) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine
Phenylmorpholines	3-Fluorophenmetrazine Fenbutrazate Fenmetramide G-130 Manifaxine Morazone Morforex Oxaflozane PD-128,907 Phendimetrazine Phenmetrazine 2-Phenyl-3,6-dimethylmorpholine Pseudophenmetrazine Radafaxine
Piperazines	2C-B-BZP 3C-PEP BZP CM156 DBL-583 GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 MeOPP MBZP oMPP Vanoxerine
Piperidines	1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine 2-Benzylpiperidine 2-Methyl-3-phenylpiperidine 3,4-Dichloromethylphenidate 4-Benzylpiperidine 4-Fluoromethylphenidate 4-Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate JZ-IV-10 Methylphenidate (Dexmethylphenidate) Nocaine Phacetoperane Pipradrol Propylphenidate SCH-5472
Pyrrolidines	2-Diphenylmethylpyrrolidine 5-DBFPV α-PPP α-PBP α-PHP α-PHPP α-PVP α-PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone
Racetams	Oxiracetam Phenylpiracetam Phenylpiracetam hydrazide
Tropanes	4-fluorotropacocaine 4'-Fluorococaine Altropane (IACFT) Brasofensine CFT (WIN 35,428) β-CIT (RTI-55) Cocaethylene Cocaine Dichloropane (RTI-111) Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (¹²³I) Norcocaine PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-120 RTI-121 (IPCIT) RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 RTI-354 RTI-371 RTI-386 Salicylmethylecgonine Tesofensine Troparil (β-CPT, WIN 35,065-2) Tropoxane WF-23 WF-33
Tryptamines	4-HO-αMT 4-Methyl-αET 4-Methyl-αMT 5-Chloro-αMT 5-Fluoro-αMT 5-MeO-αET 5-MeO-αMT 5-MeO-DIPT 6-Fluoro-αMT 7-Methyl-αET αET αMT
Others	2-MDP 3,3-Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D-161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI-52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ-7925476 Lazabemide Leptacline Lomevactone LR-5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O-2172 Oxaprotiline PNU-99,194 PRC200-SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH-232 Yohimbine
ATC code: N06B

v t e Sigma receptor modulators
σ₁	Agonists: 3-PPP 4-PPBP 5-MeO-DMT Alazocine (SKF-10047) Amantadine ANAVEX2-73 Arketamine BD-737 BD-1052 Captodiame Citalopram CGRP Cloperastine Cocaine Cutamesine (SA-4503) Cyclazocine Dehydroepiandrosterone (DHEA) (prasterone) Dehydroepiandrosterone sulfate (DHEA-S) (prasterone sulfate) Dextrallorphan Dextromethorphan (DXM) Dextrorphan (DXO) Dimemorfan Dimethyltryptamine (DMT) Ditolylguanidine (DTG) Donepezil Eliprodil Escitalopram Fabomotizole (afobazole) Fluoxetine Fluvoxamine Ifenprodil Igmesine (JO-1784) IPAB Ketamine L-687384 MDMA (midomafetamine) Memantine Methamphetamine Methoxetamine Methylphenidate Nepinalone Neuropeptide Y Noscapine OPC-14523 Opipramol Pentazocine Pentoxyverine (carbetapentane) PRE-084 Pregnenolone Pregnenolone sulfate Pridopidine Racemethorphan (methorphan) Racemorphan (morphanol) UMB-23 UMB-82 Antagonists: 3-PPP AC-927 BD-1008 BD-1031 BD-1047 BD-1060 BD-1063 BD-1067 BMY-14802 (BMS-181100) CM-156 Dup-734 E-5842 E-52862 (S1RA) Haloperidol LR-132 LR-172 MS-377 NE-100 NPC-16377 Panamesine (EMD-57455) PD-144418 Pentazocine Progesterone Rimcazole (BW-234U) Sertraline SR-31742A Allosteric modulators: Phenytoin; Positive: Methylphenylpiracetam SOMCL-668 Unknown/unsorted: 3-Methoxydextrallorphan 3-MeO-PCP 4C-T-2 4-IBP 4-IPBS 4-MeO-PCP 5-MeO-DALT 5-MeO-DiPT Amitriptyline Azidopamil Chlorpromazine Clemastine Clomipramine Clorgiline D-Deprenyl DiPT DPT Ibogaine Imipramine KCR-12-83.1 Nemonapride Noribogaine RHL-033 RS-67,333 RTI-55 Saffron Safinamide Selegiline Spipethiane Trifluoperazine W-18 YKP10A
σ₂	Agonists: 3-PPP Arketamine BD-1047 BD1063 Ditolylguanidine (DTG) DKR-1005 DKR-1051 Haloperidol Ifenprodil Ketamine MDMA (midomafetamine) Methamphetamine OPC-14523 Opipramol PB-28 Phencyclidine Siramesine (Lu 28-179) UKH-1114 Antagonists: AC-927 BD-1008 BD-1067 CM-156 CT-1812 LR-172 MIN-101 Panamesine (EMD-57455) SAS-0132 Unknown/unsorted: 3-Methoxydextrallorphan 3-MeO-PCE 4-MeO-PCP 5-MeO-DALT 5-MeO-DiPT Clemastine DiPT DPT Ibogaine Nemonapride Nepinalone Noribogaine Pentazocine RS-67,333 Safinamide TMA UMB-23 UMB-82 W-18
Unsorted	Agonists: Berberine Ethylketazocine Fourphit Metaphit Naluzotan Tapentadol Tenocyclidine Antagonists: AHD1 AZ66 Lamotrigine Naloxone SM-21 UMB-100 UMB-101 UMB-103 UMB-116 YZ-011 YZ-069 YZ-185 Allosteric modulators: SKF-83959 Unknown/unsorted: 18-Methoxycoronaridine BMY-13980 Butaclamol Caramiphen Carvotroline Chlorphenamine (chlorpheniramine) Chlorpromazine Cinnarizine Cinuperone Clocapramine Dezocine EMD-59983 Hypericin (St. John's wort) Fluphenazine Gevotroline (WY-47384) Mepyramine (pyrilamine) Molindone Perphenazine Pimozide Proadifen Promethazine Propranolol Quinidine Remoxipride SL 82.0715 SR-31747A Tiospirone (BMY-13859) Venlafaxine
See also: Receptor/signaling modulators

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Chemistry:List of cocaine analogues

Analogs sensu stricto

Cocaine Stereoisomers

Arene benzene-ring 2′, 3′, 4′ (5′ & 6′) position (aryl) substitutions

para-substituted benzoylmethylecgonines

meta-substituted benzoylmethylecgonines

ortho-substituted benzoylmethylecgonines

Manifold and termination benzoyloxy phenyl-substitutions

Benzoyl and carbomethoxy branch modifications

C1-tropane-ring hydrogen—substitutions

2β-substitutions

Bioisostere 2-position carbmethoxy-ester functional replacements

Vinylogous 2β-position carbmethoxy-ester functional replacements

N-modifications

Tricyclic cocaine analogues

8 to 2 tethered analogues

8 to 3 tethered analogues

Tropane ring contraction (azabornane) analogues

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

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

3β-Carbamoyl analogues

Phenyl 3-position linkage substitutions

3β-Alkylphenyltropane & 3β-Alkenyl analogues

6-Alkyl-3-benzyltropane analogues

Direct 2,3-pyrimidino fused

Piperidine cocaine-homologues

Cocaine hapten analogues

Structural/Functional intermediate analogues

Piperidine Analogues

Benztropine (3α-Diphenylmethoxy Tropane) Analogues

Tropanyl Isoxazoline Analogues

Alicyclic Amine Analogues

Dihydroimidazoles

Local anesthetics (not usually CNS stimulants)

See also

Notes (inclu. specific locations of citations from within references used)

References

External links

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