Rimcazole analogs attenuate the convulsive effects of cocaine: correlationwith binding to sigma receptors rather than dopamine transporters

Cocaine interacts with dopamine transporters and sigma receptors at concent rations that are achievable in vivo, suggesting that they may both be viabl e targets for the development of anti-cocaine agents. Rimeazole binds to bo th of these targets and also attenuates cocaine-induced locomotor activity and sensitization. To further characterize the mechanisms(s) underlying the attenuation of cocaine-induced convulsions and lethality, rimeazole and th ree analogs (SH3/24, SH2/21, SH1/57), with a range of affinities for dopami ne transporters and sigma receptors, were evaluated. The highly selective a nd potent sigma receptor ligand LR176 was used as a reference. Competition binding studies confirmed that the rank order of the compounds at dopamine transporters vs. sigma receptors differed, thus enabling a correlation betw een the relative anti-cocaine activities of the compounds in behavioral Stu dies and their affinities for dopamine transporters vs. sigma receptors. In behavioral studies, male Swiss Webster mice were pre-treated with one of t he compounds (0-60 mg/kg, i.p.), then challenged 15 min later with either a convulsive (60 mg/kg, i.p.) or lethal ( 125 mg/kg, i.p.) dose of cocaine. When the compounds were ranked according to their protective effect, there was a significant correlation between their anticonvulsant actions and thei r affinities for sigma receptors, but not dopamine transporters. Although t he rimeazole analogs were ineffective against the lethal effects of cocaine , the selective sigma receptor ligand LR176 provided significant protection . These data thus suggest that sigma receptors may mediate some of the toxi c effects associated with cocaine and that sigma receptor antagonists may b e developed as pharmacotherapeutic agents for this application. Published b y Elsevier Science Ltd.