title: Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine.
abstract: The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-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.
authors.affiliation: Drug Discovery Program, Departments of Neurology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Olivier
authors.initials: O
authors.lastname: Deschaux
authors.forename: Bidhan C
authors.initials: BC
authors.lastname: Bandyopadhyay
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Araldi
authors.forename: Gilberto
authors.initials: G
authors.lastname: Carmona
authors.forename: Patrik
authors.initials: P
authors.lastname: Munzar
authors.forename: Miles P
authors.initials: MP
authors.lastname: Smith
authors.forename: Robert L
authors.initials: RL
authors.lastname: Balster
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Beardsley
authors.forename: Srihari R
authors.initials: SR
authors.lastname: Tella
mesh_terms: D000818:Animals; D003042:Cocaine / Q000819:agonists* / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D004193:Discrimination Learning / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
chemical_list: D010880:Piperidines; C466798:methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate; D003042:Cocaine