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(+)-CPCA

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What is (+)-CPCA?

  • It 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. This compound was first developed as a substitute agent for cocaine.
  • Synonyms:
  1. Nocaine
  2. 263769-22-8
  3. (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester
  4. CHEMBL296019
  5. 4-(4-Chloro-phenyl)-1-methyl-piperidine-3-carboxylic acid methyl ester
  6. Methyl (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
  7. TL8002108
  8. SCHEMBL1086468
  9. DTXSID80180975
  10. 3alpha-Carbomethoxy-4beta-(4-chlorophenyl)-N-methylpiperidine
  11. ZINC4423541
  12. BDBM50099288
  13. MFCD09835335
  14. PDSP1_001293
  15. PDSP2_001277
  16. (+)-Methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate
  17. 769C228
  18. Q4540627
  19. (3R,4S)-4-(4-Chloro-phenyl)-1-methylpiperidine-3-carboxylic acid(OMe)
  20. (1S)-1alpha-Methyl-4beta-(4-chlorophenyl)piperidine-3alpha-carboxylic acid methyl ester
  21. (3R,4S)-4-(4-Chloro-phenyl)-1-methyl-piperidine-3-carboxylic acid methyl ester
  22. 1-Methyl-4beta-(4-chlorophenyl)piperidine-3alpha-carboxylic acid methyl ester
  • Molecular Weight: 267.75
(+)-CPCA

How does this drug work?

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.[1] Some sort of cholinergic effect might also be aversive. For example, muscarinic activity of benztropine analogs is known to limit their reinforcing potential.[2] 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,[3][4][5][6] (Ping and Teruo, 2003 rev).[7] Sigma receptors are not specific to cocaine, other psychostimulants like methylphenidate, methamphetamine (E. Nguyen, et al. 2005),[8] 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.[9]

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.

References

  1. Cite error: Invalid <ref> tag; no text was provided for refs named Lomenzo

Portions of content adapted from Wikipedia's article on (+)-CPCA which is released under the CC BY-SA 3.0.

 

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