(+)-CPCA
Clinical data
ATC code
  • none
Identifiers
  • Methyl (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H18ClNO2
Molar mass267.75 g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1)[C@@H]2[C@@H](C(=O)OC)CN(C)CC2
  • InChI=1S/C14H18ClNO2/c1-16-8-7-12(13(9-16)14(17)18-2)10-3-5-11(15)6-4-10/h3-6,12-13H,7-9H2,1-2H3/t12-,13+/m1/s1 ☒N
  • Key:GDFVYUDIAQQDTA-OLZOCXBDSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

(+)-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.

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.

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
Cocaine119177275
(–)-cis-CPCA9839067
(+)-CPCA905900276

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)
RNEDA5HT
CO2Me252 → 7.9233 → 2798490 → 434
CH2OH198 → 69497 → 8361550 → 239
Oxadiazole256 → 34187 → 1895960 → 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
CO2Me2338490252
CONMe2214018900569
CH2OAc599901235
CH2OCH2CH=CH26023120
CH2CO2Et79191101
CH2CONMe216199446
Heterocycle443252
CH2CH2CO2Me6825531
trans-CH=CHCO2Me53501272
Prn202286.5
(CH2)3OH162810564

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

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.

See also

References

  1. 1 2 Mobele BI, Kinahan T, Ulysse LG, Gagnier SV, Ironside MD, Knox GS, Mohammadi F (2006). "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. doi:10.1021/op060114g.
  2. ↑ Kozikowski AP, Araldi GL, Boja J, Meil WM, Johnson KM, Flippen-Anderson JL, et al. (May 1998). "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. doi:10.1021/jm980028+. PMID 9599245.
  3. 1 2 EP 2617704, Shao, Liming; Wang, Fengjiang & Malcolm, Scott Christopher et al., "Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors", published 2017-06-28, assigned to Sunovion Pharmaceuticals Inc.
  4. ↑ Provencher BA, Eshleman AJ, Johnson RA, Shi X, Kryatova O, Nelson J, et al. (October 2018). "Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter". Journal of Medicinal Chemistry. 61 (20): 9121–9131. doi:10.1021/acs.jmedchem.8b00542. PMID 30240563. S2CID 52312790.
  5. ↑ Jiang S, Chang AC, Abraham P, Kuhar MJ, Carroll FI (December 1998). "Synthesis and transporter binding properties of (R)-2β,3β- and (R)-2α,3α-diaryltropanes". Bioorganic & Medicinal Chemistry Letters. 8 (24): 3689–92. doi:10.1016/s0960-894x(98)00673-8. PMID 9934496.
  6. ↑ Hauck AE, Giam CS (1980). "Regioselective nucleophilic addition of organolithium compounds to 3-(4,4-dimethyloxazolin-2-yl)pyridine". Journal of the Chemical Society, Perkin Transactions 1: 2070. doi:10.1039/p19800002070.
  7. ↑ Shao L, Li W, Xie Q, Yin H (February 2014). "Triple reuptake inhibitors: a patent review (2006 - 2012)". Expert Opinion on Therapeutic Patents. 24 (2): 131–154. doi:10.1517/13543776.2014.859676. PMID 24289044. S2CID 1825304.
  8. ↑ US 7560562, Wätjen, Frank, "Piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2009-07-14, assigned to Neuroesearch AS
  9. ↑ Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM (March 1996). "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. doi:10.1021/jm950697c. PMID 8632426.
  10. ↑ Schweri MM, Deutsch HM, Massey AT, Holtzman SG (May 2002). "Biochemical and behavioral characterization of novel methylphenidate analogs". The Journal of Pharmacology and Experimental Therapeutics. 301 (2): 527–535. doi:10.1124/jpet.301.2.527. PMID 11961053.
  11. ↑ Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML (March 2005). "Synthesis and biological evaluation of meperidine analogues at monoamine transporters". Journal of Medicinal Chemistry. 48 (5): 1336–1343. doi:10.1021/jm0401614. PMID 15743177.
  12. ↑ Rhoden JB, Bouvet M, Izenwasser S, Wade D, Lomenzo SA, Trudell ML (October 2005). "Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry. 13 (19): 5623–5634. doi:10.1016/j.bmc.2005.05.025. PMID 15993612.
  13. ↑ Shao L, Hewitt MC, Wang F, Malcolm SC, Ma J, Campbell JE, et al. (March 2011). "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. doi:10.1016/j.bmcl.2011.01.016. PMID 21310609.
  14. ↑ Shao L, Hewitt MC, Wang F, Malcolm SC, Ma J, Campbell JE, et al. (March 2011). "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. doi:10.1016/j.bmcl.2011.01.019. PMID 21310612.
  15. 1 2 Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML (March 2005). "Synthesis and biological evaluation of meperidine analogues at monoamine transporters". Journal of Medicinal Chemistry. 48 (5): 1336–1343. doi:10.1021/jm0401614. PMID 15743177.
  16. ↑ Zou MF, Cao J, Kopajtic T, Desai RI, Katz JL, Newman AH (October 2006). "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. doi:10.1021/jm060762q. PMID 17034144.
  17. ↑ Matsumoto RR, Hewett KL, Pouw B, Bowen WD, Husbands SM, Cao JJ, Newman AH (December 2001). "Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters". Neuropharmacology. 41 (7): 878–886. doi:10.1016/S0028-3908(01)00116-2. PMID 11684152. S2CID 44328858.
  18. ↑ Matsumoto RR, McCracken KA, Friedman MJ, Pouw B, De Costa BR, Bowen WD (May 2001). "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. doi:10.1016/S0014-2999(01)00968-2. PMID 11426838.
  19. ↑ Matsumoto RR, McCracken KA, Pouw B, Zhang Y, Bowen WD (June 2002). "Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides". Neuropharmacology. 42 (8): 1043–1055. doi:10.1016/S0028-3908(02)00056-4. PMID 12128006. S2CID 34846910.
  20. ↑ Matsumoto RR, Liu Y, Lerner M, Howard EW, Brackett DJ (May 2003). "Sigma receptors: potential medications development target for anti-cocaine agents". European Journal of Pharmacology. 469 (1–3): 1–12. doi:10.1016/S0014-2999(03)01723-0. PMID 12782179.
  21. ↑ Su TP, Hayashi T (October 2003). "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. doi:10.2174/0929867033456783. PMID 12871086.
  22. ↑ Nguyen EC, McCracken KA, Liu Y, Pouw B, Matsumoto RR (October 2005). "Involvement of sigma (sigma) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies". Neuropharmacology. 49 (5): 638–645. doi:10.1016/j.neuropharm.2005.04.016. PMID 15939443. S2CID 41068558.
  23. ↑ Wang J, Mack AL, Coop A, Matsumoto RR (November 2007). "Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice". European Neuropsychopharmacology. 17 (11): 708–716. doi:10.1016/j.euroneuro.2007.02.007. PMC 4041597. PMID 17376658.
  24. ↑ Xu L, Trudell ML (November 1996). "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. doi:10.1002/jhet.5570330676.
  25. ↑ WO application 0232870, Ward, Neal, "Process of the preparation of 3-substituted-4-aryl piperidine compounds", published 2002-04-25, assigned to SmithKline Beecham plc
  26. ↑ WO application 0129032, Crowe, David; Ward, Neal & Wells, Andrew Stephen, "Process for the preparation of paroxetine", published 2001-04-26, assigned to SmithKline Beecham plc
  27. ↑ WO 0117966, Crowe, David; Jones, David Alan & Ward, Neal, "Process for the preparation of 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine", published 2001-03-15, assigned to SmithKline Beecham plc
  28. ↑ "Copper-Catalyzed Conjugate Addition to α,β-Unsaturated Carbonyl Compounds".
  29. ↑ Petukhov PA, Zhang J, Kozikowski AP, Wang CZ, Ye YP, Johnson KM, Tella SR (July 2002). "SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement". Journal of Medicinal Chemistry. 45 (15): 3161–3170. doi:10.1021/jm0200153. PMID 12109901.
  30. ↑ Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, et al. (January 2007). "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". Journal of Medicinal Chemistry. 50 (2): 219–232. doi:10.1021/jm0608614. PMID 17228864.
  31. ↑ Wang S, Sakamuri S, Enyedy IJ, Kozikowski AP, Deschaux O, Bandyopadhyay BC, et al. (February 2000). "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. doi:10.1021/jm990516x. PMID 10669562.
  32. ↑ Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, et al. (September 2001). "Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice". Nature Neuroscience. 4 (9): 873–874. doi:10.1038/nn0901-873. PMID 11528416. S2CID 1314227.
  33. ↑ Petukhov PA, Zhang J, Wang CZ, Ye YP, Johnson KM, Kozikowski AP (June 2004). "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. doi:10.1021/jm0303296. PMID 15163183.
  34. 1 2 Yuan H, Kozikowski AP, Petukhov PA (December 2004). "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. doi:10.1021/jm049544s. PMID 15566285.
  35. 1 2 Lieske SF, Yang B, Eldefrawi ME, MacKerell AD, Wright J (March 1998). "(-)-3 beta-Substituted ecgonine methyl esters as inhibitors for cocaine binding and dopamine uptake". Journal of Medicinal Chemistry. 41 (6): 864–876. doi:10.1021/jm970025h. PMID 9526561.
  36. ↑ Petukhov PA, Zhang M, Johnson KJ, Tella SR, Kozikowski AP (August 2001). "Sar studies of piperidine-based analogues of cocaine. Part 3: oxadiazoles". Bioorganic & Medicinal Chemistry Letters. 11 (16): 2079–2083. doi:10.1016/S0960-894X(01)00379-1. PMID 11514143.
  37. ↑ Tamiz AP, Bandyopadhyay BC, Zhang J, Flippen-Anderson JL, Zhang M, Wang CZ, et al. (May 2001). "Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors". Journal of Medicinal Chemistry. 44 (10): 1615–1622. doi:10.1021/jm000552s. PMID 11334571.
  38. ↑ Amat M, Bosch J, Hidalgo J, Cantó M, Pérez M, Llor N, et al. (May 2000). "Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine". The Journal of Organic Chemistry. 65 (10): 3074–3084. doi:10.1021/jo991816p. PMID 10814199.
  39. ↑ Johnson TA, Jang DO, Slafer BW, Curtis MD, Beak P (October 2002). "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. doi:10.1021/ja0271375. PMID 12296735.
  40. ↑ Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, et al. (March 2000). "Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors". Journal of Medicinal Chemistry. 43 (6): 1215–1222. doi:10.1021/jm9905561. PMID 10737754.
  41. ↑ Zhou J, He R, Johnson KM, Ye Y, Kozikowski AP (November 2004). "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. doi:10.1021/jm040117o. PMC 1395211. PMID 15537337.
  42. ↑ He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP (December 2005). "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. doi:10.1021/jm050694s. PMID 16335921.
  43. ↑ Musachio JL, Hong J, Ichise M, Seneca N, Brown AK, Liow JS, et al. (June 2006). "Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors". Bioorganic & Medicinal Chemistry Letters. 16 (12): 3101–3104. doi:10.1016/j.bmcl.2006.03.066. PMID 16621532.
  44. ↑ Zhou J (December 2004). "Norepinephrine transporter inhibitors and their therapeutic potential". Drugs of the Future. 29 (12): 1235–1244. doi:10.1358/dof.2004.029.12.855246. PMC 1518795. PMID 16871320.
  45. ↑ Yuan H, Petukhov PA (December 2006). "Improved 3D-QSAR CoMFA of the dopamine transporter blockers with multiple conformations using the genetic algorithm". Bioorganic & Medicinal Chemistry Letters. 16 (24): 6267–6272. doi:10.1016/j.bmcl.2006.09.037. PMID 17027270.
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