Chemistry:(+)-CPCA

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Short description: Stimulant drug
(+)-CPCA
(+)-CPCA.svg
Clinical data
ATC code
  • none
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC14H18ClNO2
Molar mass267.75 g·mol−1
3D model (JSmol)
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(+)-CPCA (nocaine, 3α-carbomethoxy-4β-(4-chlorophenyl)-N-methylpiperidine aka CTDP 31,446[1] ) is a stimulant drug similar in structure to pethidine (an opioid that possesses NDRI actions) and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton.[2] This compound was first developed as a substitute agent for cocaine.

Since this time many substituted phenylpiperidine derivatives have been discovered, hybridizing the basic nocaine structure with that of other similar molecules such as methylphenidate, meperidine and modafinil to create a large family of derivatives with a range of activity profiles and potential applications. This is a significant field of research with much work ongoing, and dozens of novel compounds have been developed although none have yet come to market.

The nocaine family includes a diverse assortment of piperidine based cocaine mimics. The parent compound nocaine was developed in an attempt to develop a substitute drug for cocaine for the treatment of addiction, and was found to substitute for cocaine in animal models while having significantly less abuse potential itself.

Background

Although Kozikowski reported compound with chlorine in 1998, plain phenyl was reported earlier than this by Plati.

Although novel ways to produce these compound exist, background stems from arecoline chemistry. E.g. paroxetine (Paxil) and femoxetine also from this arena of CNS chemicals. These serotonin based antidepressants, in case of Paxil N-normethyl also some acetylcholinergic according to texts.[citation needed]

Further nocaine derivatives was developed for treating addiction from Kozikowski's teachings:[3] Smith specifically states that the butyrophenone analog of nocaine is an active agent, as well as specifying pthalimide type alkylamino agents.[citation needed]

Butyrophenone-Nocaine

Further support lends a scale-up process that also relies on arecoline, which is toxic and already active pharmaceutical salt:[1]

The Ketanserin analog devised by Peter Meltzer uses an altogether different methodology of synthesis:[4] The same procedure was employed years earlier for GSK1360707F, and was known from before this from RTI diaryltropanes.[5] Thus, these methods is now well known in the art and does not necessarily rely on the use of arecoline as a starting material.

The Warner-Lambert Butler synthesis for example uses a 4-phenylnicotinic acid starting material: U.S. Patent 4,745,123 citing:[6]

3',4'-Dichloro Advocacy

Thue method of improving the cited Ki by 3',4'-dichlorophenyl is now well known in the art and is heavily patented.[7]

  1. piperidine-brasofensine U.S. Patent 6,376,673
  2. piperidine-tesofensine[8] U.S. Patent 20,060,094,759
  3. Ritalin,[9][10]
  4. Meperidine,[11][12]
  5. sertraline
  6. indatraline
  7. dichloroisoprenaline
  8. sibutramine:[13][14]
  9. mazindol
  10. dichloropane
  11. tramadol[3]
  12. Amitifadine
  13. Diclofensine
  14. JNJ-7925476
  15. venlafaxine

Pharmacology

Like cocaine, (−)-cis-CPCA and (+)-CPCA bind to the dopamine transporter and inhibit dopamine uptake, stimulate motor activity in rodents and completely substitute for cocaine in discrimination tests. Pretreatment with (−)-cis-CPCA or (+)-CPCA enhances the cocaine discriminative stimulus in rats. However, there are a number of differences; the locomotor stimulant effects of the piperidine derivatives are much less than those induced by cocaine, and pretreating mice with (−)-cis-CPCA or (+)-CPCA does not increase cocaine induced convulsions, and actually reduced cocaine induced locomotor stimulation. The (−)-cis-CPCA isomer has similar reinforcing effects to cocaine as shown by fixed-ratio self-administration tests in rats, but (+)-CPCA has a flat dose-response curve, and similarly while (−)-cis-CPCA and cocaine had nearly identical break points in a "punished responding" (?) self-administration test, (+)-CPCA had a lower break point than either of the other drugs.

Monoamine Reuptake Activity (nM)
Compound [3H]NE [3H]5-HT [3H]DA
Cocaine 119 177 275
(−)-cis-CPCA 98 390 67
(+)-CPCA 90 5900 276

The generally lower efficacy of (+)-CPCA in locomotor and methamphetamine discrimination tests could result from the differential selectivity of the two isomers for the DAT relative to the SERT. That is, if serotonin receptor activation is requisite for maximal efficacy, the difference SERT affinity between (−)-cis-CPCA and (+)-CPCA might play a contributory role in accounting for the differences in the observed pharmacology. Catecholamine selective drugs, like TMP (methylphenidate), are reported to possess decent abuse potential though, so it is not easy to gauge why (+)-CPCA does not entice a strong self-administration propensity.

A possible explanation might be nocaine preferentially binds to the ↓ DAT, in which case it would be expected to behave somewhat differently from cocaine.[15] Some sort of cholinergic effect might also be aversive. For example, muscarinic activity of benztropine analogs is known to limit their reinforcing potential.[16] Ion-channel activity is another factor that can be used to explain certain differences in pharmacology.

It is possible that sigma receptor activity might also account for some of the differences between cocaine and these piperidine mimics (R. Matsumoto, et al. 2001,[17][18][19][20] (Ping and Teruo, 2003 rev).[21] Sigma receptors are not specific to cocaine, other psychostimulants like methylphenidate, methamphetamine (E. Nguyen, et al. 2005),[22] and phencyclidine are also linked to this neural target. An increased understanding of this receptor recently led to a novel AD being reported that is based around its pharmacology.[23]

In summary, (+)-CPCA has lower potency and efficacy than cocaine in increasing locomotor activity in rodents. (+)-CPCA only manages to produce partial methamphetamine-like discriminative stimulus effects, although it is fully cocaine-like in cocaine-trained animals. (+)-CPCA has lower reinforcing potential than cocaine as assessed by fixed and progressive ratio IV self-administration tests in rats, with its reinforcing effects confirmed by rhesus monkeys. Furthermore, (+)-CPCA dose dependently antagonizes cocaine-induced locomotion and potentiates the discriminative stimulus effects of a low dose of cocaine. (+)-CPCA, unlike cocaine, does not enhance cocaine-induced convulsions. These results suggest that (+)-CPCA completely mimics certain behavioral actions of cocaine, whereas acting like a weak partial agonist in others, including its ability to attenuate cocaine-induced increase in locomotion and to serve as a positive reinforcing agent in rodents. Thus, (+)-CPCA may have potential utility in the treatment of cocaine addiction, and also offer valuable pharmacological information, furthering our understanding of cocaine's mechanism of action, because it exhibits fundamental differences from other related DARI molecules.

Chemistry

Routes of synthesis

The arecoline route goes the same as for RTI-31 starting from Methylecgonidine.[24] Trudell lays down the groundwork for the correct procedure that was then heavily patented by SKF.

Patented methods reported

  1. Ward & Crowe SKF improved method: U.S. Patent 6,172,233[25][26][27]

3 theoretical improvements over the earlier historical attempts of the work of Plati & Clarke:

  1. The solvent is apolar whereas for forming the Grignard reagent the solvent needs to be ether, which is removed prior to the conjugate addition.
  2. The temperature for forming the Grignard reagent needs to be reflux whereas the temperature needs to be refrigerated for the conjugate addition.
  3. A catalytic amount of CuCl can encourage soft over hard addition.[28]

Ester and amine modifications

A series of novel N- and 3α-modified nocaine analogs were synthesized and tested for their SNDRI activity and behavioral properties in mice.[29]

The rational design of ligands with a predetermined potency at and selectivity for monoamine transporters is hindered by the lack of knowledge about the 3D structure of these targets. In cases where the 3D structure of the binding site in a target protein is not well defined, as is the case for the monoamine transporter proteins, one can perform ligand-based design to develop a pharmacophore. That is, by studying the conformational properties of a series of pharmacologically similar compounds, one can form hypotheses regarding the pharmacophore.[30] Most of the potent tropane-based inhibitors, inc. coca, are believed to have at least 3 major interactions with the transporter binding site: one ionic or H-bonding interaction at the basic nitrogen, one dipole-dipole or H-bonding interaction of the ester group, and an interaction of the aryl group with a lipophilic binding pocket. This model was successfully used for the design of a novel piperidine-based DAT inhibitor, that is economically affordable to manufacture.[31]

Although the in vivo metabolism of (+)-CPCA is also likely to involve N-demethylation, metabolism to the corresponding free acid, to give a compound inactive at all monoamine transporters, will probably be the predominant pathway in vivo. It was reasoned that metabolism via esterase action can be avoided by replacing the ester group with a bioisosteric group that is more stable to metabolic degradation. In previous studies, it was found that oxadiazole, although cocaine-like in activity, exhibits a significantly longer duration of action due to slower rate of metabolism. In general, relative to the corresponding N-methyl compounds, the norpiperidines exhibited an increased activity at the SERT/NET and only modest changes at the DAT.

Ki (nM)
R NE DA 5HT
CO2Me 252 → 7.9 233 → 279 8490 → 434
CH2OH 198 → 69 497 → 836 1550 → 239
Oxadiazole 256 → 34 187 → 189 5960 → 373

An interesting difference between cocaine, ester 1a, alcohol 2a, and norester 1b is that the latter two compounds are substantially longer acting than cocaine in locomotor activity tests in mice. Although prolonged action is anticipated from compounds like alcohol 2a and oxadiazole 3a which lack the 3α ester group and so are more difficult to metabolise, this is not expected for the norester 1b, because the 3α ester group should be just as easily hydrolysed as the ester group of cocaine and 1a. Another result of N-demethylation is an initial depressant action of 1b followed by delayed locomotor stimulation, which might be due to interaction with GABA receptors or mGlu5.[32]

3β-Substituted nocaine ligand design

In an earlier study, it was found that 3α-amido and bulky 3α-oxadiazoyl nocaine ligands, which possess greater stability relative to the ester functional group, and are therefore more attractive as potential therapies, are inactive. This result led to the hypothesis that the binding site of the DAT and NET in close proximity to the 3α-position of the piperidine ring is compact and cannot accommodate bulky, sterically occluded substituents, like the 3-substituted 1,2,4-oxadiazolyl groups. It was reasoned that introduction of a methylene spacer would confer improved monoamine transporter binding affinity upon the resultant molecules.[33]

Structure of 3α-Substituted nocaine
R [3H]DA [3H]5-HT [3H]NE
CO2Me 233 8490 252
CONMe2 2140 18900 569
CH2OAc 599 901 235
CH2OCH2CH=CH2 60 231 20
CH2CO2Et 79 191 101
CH2CONMe2 16 1994 46
Heterocycle 44 32 52
CH2CH2CO2Me 68 255 31
trans-CH=CHCO2Me 53 501 272
Prn 20 228 6.5
(CH2)3OH 16 2810 564

One of the possible reasons that the C2–C3 compounds are more active than the C1 compounds is that the polar group present in the more flexible 3α-appendage of the C2–C3 ligands is able to avoid unfavorable interactions with the binding site in close proximity to the piperidine ring. For the same reason the appendage in the C2–C3 series may more closely, but not precisely, mimic the binding mode of the more active SS based ligands, and possibly even transfer over to tropane based compounds.

To better understand the difference between the C1 and the C2–C3 series, the compounds were energy minimized and flexibly superimposed on WIN-35,428. The resulting overlay shows that only the C2–C3 ligands are able to adopt a conformation in which the polar group of the 3α-substituent occupies the position proximal to that of the 2β-polar group in WIN35428.

Nocaine: sulfur appendage

Compound 16e

JZ-IV-10 chemical structure.png

Pharmacophore

A generally recognized pharmacophore model for cocaine and phenyltropanes comprises two electrostatic interactions of the basic nitrogen and the ester group of the C-2 substituent, and one hydrophobic interaction of the C-3 aryl group.[34] This model has been disputed because of the finding that in certain compounds neither the basic N nor the ester group was necessary for high binding affinity and inhibition of MAR. Instead, a hydrophobic pocket was proposed to exist in the vicinity of the C-2 carbon. Carroll et al., however, provided further evidence for an electrostatic interaction at the C-2β-position in a later study.

Other models proposed for the DAT binding site include a linear fashion binding pocket for the 3β-substituted phenyltropane analogs,[35] and a prohibited conical region about 5.5–10 Å distant from the 3α-substituted piperidine ring.[36] Noticeably, high potency at the DAT of dimeric piperidine-based esters and amides suggested that the flexible linker combining the two piperidine units was able to adjust its orientation and to avoid unfavorable interactions with the binding site.[37] All these lines of evidence suggest that the DAT binding site is much more complicated than the proposed pharmacophore models.

In an attempt to uncover the details of the DAT binding site, a number of 3D-QSAR studies were performed. Several QSAR/CoMFA studies focused on phenyltropanes concluded that an increased negative electrostatic potential in the regions around the 3β-substituent of the tropane ring and the para-position of the phenyl ring favored high potency in inhibiting the MATs. Wright et al. studied the role of the 3β-substituent of tropanes in binding to the DAT and blocking DA re-uptake. Their CoMFA model indicated that the 3β-substituent binding site is barrel-shaped and hydrophobic interactions make a dominant contribution to the binding,[35] which is consistent with the studies of 3α-substituted tropane analogs reported by Newman et al. Newman and co-authors also studied N-substituted tropanes and concluded that the steric interaction of the N-substituent with the DAT is a principal factor for the binding affinity.

Yuan.gif

See also

References

  1. ↑ 1.0 1.1 "Process Development toward the Pilot Scale Synthesis of the Piperidine-Based Cocaine Analogue and Potent Dopamine and Norepinephrine Reuptake Inhibitor CTDP 31,446". Organic Process Research & Development 10 (5): 914–920. 2006. doi:10.1021/op060114g. 
  2. ↑ "Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton". Journal of Medicinal Chemistry 41 (11): 1962–1969. May 1998. doi:10.1021/jm980028+. PMID 9599245. 
  3. ↑ 3.0 3.1 Shao, Liming; Fengjiang Wang & Scott Christopher Malcolm et al., "Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors", EP patent 2617704, published 2017-06-28, assigned to Sunovion Pharmaceuticals Inc.
  4. ↑ "Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter". Journal of Medicinal Chemistry 61 (20): 9121–9131. October 2018. doi:10.1021/acs.jmedchem.8b00542. PMID 30240563. 
  5. ↑ "Synthesis and transporter binding properties of (R)-2β,3β- and (R)-2α,3α-diaryltropanes". Bioorganic & Medicinal Chemistry Letters 8 (24): 3689–92. December 1998. doi:10.1016/s0960-894x(98)00673-8. PMID 9934496. 
  6. ↑ "Regioselective nucleophilic addition of organolithium compounds to 3-(4,4-dimethyloxazolin-2-yl)pyridine". Journal of the Chemical Society, Perkin Transactions 1: 2070. 1980. doi:10.1039/p19800002070. 
  7. ↑ "Triple reuptake inhibitors: a patent review (2006 - 2012)". Expert Opinion on Therapeutic Patents 24 (2): 131–154. February 2014. doi:10.1517/13543776.2014.859676. PMID 24289044. 
  8. ↑ Wätjen, Frank, "Piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", US patent 7560562, published 2009-07-14, assigned to Neuroesearch AS
  9. ↑ "Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs". Journal of Medicinal Chemistry 39 (6): 1201–1209. March 1996. doi:10.1021/jm950697c. PMID 8632426. 
  10. ↑ "Biochemical and behavioral characterization of novel methylphenidate analogs". The Journal of Pharmacology and Experimental Therapeutics 301 (2): 527–535. May 2002. doi:10.1124/jpet.301.2.527. PMID 11961053. 
  11. ↑ "Synthesis and biological evaluation of meperidine analogues at monoamine transporters". Journal of Medicinal Chemistry 48 (5): 1336–1343. March 2005. doi:10.1021/jm0401614. PMID 15743177. 
  12. ↑ "Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry 13 (19): 5623–5634. October 2005. doi:10.1016/j.bmc.2005.05.025. PMID 15993612. 
  13. ↑ "Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters 21 (5): 1438–1441. March 2011. doi:10.1016/j.bmcl.2011.01.016. PMID 21310609. 
  14. ↑ "Discovery of N-methyl-1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters 21 (5): 1434–1437. March 2011. doi:10.1016/j.bmcl.2011.01.019. PMID 21310612. 
  15. ↑ 15.0 15.1 "Synthesis and biological evaluation of meperidine analogues at monoamine transporters". Journal of Medicinal Chemistry 48 (5): 1336–1343. March 2005. doi:10.1021/jm0401614. PMID 15743177. 
  16. ↑ "Structure-activity relationship studies on a novel series of (S)-2beta-substituted 3alpha-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues for in vivo investigation". Journal of Medicinal Chemistry 49 (21): 6391–6399. October 2006. doi:10.1021/jm060762q. PMID 17034144. 
  17. ↑ "Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters". Neuropharmacology 41 (7): 878–886. December 2001. doi:10.1016/S0028-3908(01)00116-2. PMID 11684152. 
  18. ↑ "Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma1 receptors produce anti-cocaine effects in mice". European Journal of Pharmacology 419 (2–3): 163–174. May 2001. doi:10.1016/S0014-2999(01)00968-2. PMID 11426838. 
  19. ↑ "Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides". Neuropharmacology 42 (8): 1043–1055. June 2002. doi:10.1016/S0028-3908(02)00056-4. PMID 12128006. 
  20. ↑ "Sigma receptors: potential medications development target for anti-cocaine agents". European Journal of Pharmacology 469 (1–3): 1–12. May 2003. doi:10.1016/S0014-2999(03)01723-0. PMID 12782179. 
  21. ↑ "Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction". Current Medicinal Chemistry 10 (20): 2073–2080. October 2003. doi:10.2174/0929867033456783. PMID 12871086. https://zenodo.org/record/1235850. 
  22. ↑ "Involvement of sigma (sigma) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies". Neuropharmacology 49 (5): 638–645. October 2005. doi:10.1016/j.neuropharm.2005.04.016. PMID 15939443. 
  23. ↑ "Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice". European Neuropsychopharmacology 17 (11): 708–716. November 2007. doi:10.1016/j.euroneuro.2007.02.007. PMID 17376658. 
  24. ↑ "Stereoselective synthesis of 2β-carbomethoxy-3β-phenyltropane derivatives. Enhanced stereoselectivity observed for the conjugate addition reaction of phenylmagnesium bromide derivatives with anhydro dichloromethane". Journal of Heterocyclic Chemistry 33 (6): 2037–2039. November 1996. doi:10.1002/jhet.5570330676. 
  25. ↑ Ward, Neal, "Process of the preparation of 3-substituted-4-aryl piperidine compounds", WO patent application 0232870, published 2002-04-25, assigned to SmithKline Beecham plc
  26. ↑ Crowe, David; Neal Ward & Andrew Stephen Wells, "Process for the preparation of paroxetine", WO patent application 0129032, published 2001-04-26, assigned to SmithKline Beecham plc
  27. ↑ Crowe, David; David Alan Jones & Neal Ward, "Process for the preparation of 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine", WO patent 0117966, published 2001-03-15, assigned to SmithKline Beecham plc
  28. ↑ "Copper-Catalyzed Conjugate Addition to α,β-Unsaturated Carbonyl Compounds". https://www.organic-chemistry.org/Highlights/2005/04February.shtm. 
  29. ↑ "SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement". Journal of Medicinal Chemistry 45 (15): 3161–3170. July 2002. doi:10.1021/jm0200153. PMID 12109901. 
  30. ↑ "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". Journal of Medicinal Chemistry 50 (2): 219–232. January 2007. doi:10.1021/jm0608614. PMID 17228864. 
  31. ↑ "Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies". Journal of Medicinal Chemistry 43 (3): 351–360. February 2000. doi:10.1021/jm990516x. PMID 10669562. 
  32. ↑ "Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice". Nature Neuroscience 4 (9): 873–874. September 2001. doi:10.1038/nn0901-873. PMID 11528416. 
  33. ↑ "Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring". Journal of Medicinal Chemistry 47 (12): 3009–3018. June 2004. doi:10.1021/jm0303296. PMID 15163183. 
  34. ↑ 34.0 34.1 "CoMFA study of piperidine analogues of cocaine at the dopamine transporter: exploring the binding mode of the 3 alpha-substituent of the piperidine ring using pharmacophore-based flexible alignment". Journal of Medicinal Chemistry 47 (25): 6137–6143. December 2004. doi:10.1021/jm049544s. PMID 15566285. 
  35. ↑ 35.0 35.1 "(-)-3 beta-Substituted ecgonine methyl esters as inhibitors for cocaine binding and dopamine uptake". Journal of Medicinal Chemistry 41 (6): 864–876. March 1998. doi:10.1021/jm970025h. PMID 9526561. 
  36. ↑ "Sar studies of piperidine-based analogues of cocaine. Part 3: oxadiazoles". Bioorganic & Medicinal Chemistry Letters 11 (16): 2079–2083. August 2001. doi:10.1016/S0960-894X(01)00379-1. PMID 11514143. 
  37. ↑ "Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors". Journal of Medicinal Chemistry 44 (10): 1615–1622. May 2001. doi:10.1021/jm000552s. PMID 11334571. 
  38. ↑ "Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine". The Journal of Organic Chemistry 65 (10): 3074–3084. May 2000. doi:10.1021/jo991816p. PMID 10814199. 
  39. ↑ "Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines, pyrrolidines, and pyrimidinones". Journal of the American Chemical Society 124 (39): 11689–11698. October 2002. doi:10.1021/ja0271375. PMID 12296735. 
  40. ↑ "Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors". Journal of Medicinal Chemistry 43 (6): 1215–1222. March 2000. doi:10.1021/jm9905561. PMID 10737754. 
  41. ↑ "Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization". Journal of Medicinal Chemistry 47 (24): 5821–5824. November 2004. doi:10.1021/jm040117o. PMID 15537337. 
  42. ↑ "Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors". Journal of Medicinal Chemistry 48 (25): 7970–7979. December 2005. doi:10.1021/jm050694s. PMID 16335921. 
  43. ↑ "Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors". Bioorganic & Medicinal Chemistry Letters 16 (12): 3101–3104. June 2006. doi:10.1016/j.bmcl.2006.03.066. PMID 16621532. 
  44. ↑ "Norepinephrine transporter inhibitors and their therapeutic potential". Drugs of the Future 29 (12): 1235–1244. December 2004. doi:10.1358/dof.2004.029.12.855246. PMID 16871320. 
  45. ↑ "Improved 3D-QSAR CoMFA of the dopamine transporter blockers with multiple conformations using the genetic algorithm". Bioorganic & Medicinal Chemistry Letters 16 (24): 6267–6272. December 2006. doi:10.1016/j.bmcl.2006.09.037. PMID 17027270. 



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