Mixed cocaine agonist/antagonist properties of (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate, a piperidine-based analog of cocaine

Alan P. Kozikowski, Kenneth M. Johnson, Olivier Deschaux, Bidhan C. Bandyopadhyay, Gian Luca Araldi, Gilberto Carmona, Patrik Munzar, Miles P. Smith, Robert L. Balster, Patrick M. Beardsley, Srihari R. Tella

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylic acid [(+)-CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly, pretreatment with (+)-CPCA dose dependently blocked the locomotor stimulant effects of cocaine in rats. (+)-CPCA completely substituted for cocaine in drug discrimination tests, although it was about 3 times less potent than cocaine. It was also self-administered by rats. Unexpectedly, (+)-CPCA did not enhance cocaine-induced convulsions in mice. As expected from rodent studies, rhesus monkeys readily self-administered (+)-CPCA. However, compared with cocaine, (+)-CPCA showed limited reinforcing properties in rats as assessed by both fixed and progressive ratio intravenous drug self-administration tests. These results collectively suggest that (+)-CPCA has an atypical pharmacological profile having both cocaine-like "agonist" and some cocaine "antagonist" properties. These properties of (+)-CPCA suggest that it may have utility in the treatment of cocaine craving and dependence.

Original languageEnglish (US)
Pages (from-to)143-150
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume305
Issue number1
DOIs
StatePublished - Apr 1 2003

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Kozikowski, A. P., Johnson, K. M., Deschaux, O., Bandyopadhyay, B. C., Araldi, G. L., Carmona, G., Munzar, P., Smith, M. P., Balster, R. L., Beardsley, P. M., & Tella, S. R. (2003). Mixed cocaine agonist/antagonist properties of (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate, a piperidine-based analog of cocaine. Journal of Pharmacology and Experimental Therapeutics, 305(1), 143-150. https://doi.org/10.1124/jpet.102.046318