Vol. 305, Issue 1, 143-150, April 2003

Mixed Cocaine Agonist/Antagonist Properties of (+)-Methyl 4-(4-Chlorophenyl)-1-methylpiperidine-3-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 and Srihari R. Tella

Drug Discovery Program, Departments of Neurology (A.P.K.) and Pharmacology (S.R.T., O.D., B.C.B.), Georgetown University Medical Center, Washington, DC; Department of Pharmacology and Toxicology (K.M.J.), University of Texas Medical Branch, Galveston, Texas; National Institute on Drug Abuse, Behavioral Neuroscience Branch, Preclinical Pharmacology Section (G.C., P.M.), National Institutes of Health, Baltimore, Maryland; Biostream Therapeutics, Inc. (M.P.S.), Cambridge, Massachusetts; and Institute for Drug and Alcohol Studies (R.L.B.) and Department of Pharmacology and Toxicology (P.M.B.), Virginia Commonwealth University, Richmond, Virginia

The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-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.