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

Abstract

Cocaine interacts with dopamine transporters and σ receptors at concentrations that are achievable in vivo, suggesting that they may both be viable targets for the development of anti-cocaine agents. Rimcazole binds to both of these targets and also attenuates cocaine-induced locomotor activity and sensitization. To further characterize the mechanism(s) underlying the attenuation of cocaine-induced convulsions and lethality, rimcazole and three analogs (SH3/24, SH2/21, SH1/57), with a range of affinities for dopamine transporters and σ receptors, were evaluated. The highly selective and potent σ receptor ligand LR176 was used as a reference. Competition binding studies confirmed that the rank order of the compounds at dopamine transporters vs. σ receptors differed, thus enabling a correlation between the relative anti-cocaine activities of the compounds in behavioral studies and their affinities for dopamine transporters vs. σ receptors. In behavioral studies, male Swiss Webster mice were pre-treated with one of the 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 their affinities for σ receptors, but not dopamine transporters. Although the rimcazole analogs were ineffective against the lethal effects of cocaine, the selective σ receptor ligand LR176 provided significant protection. These data thus suggest that σ receptors may mediate some of the toxic effects associated with cocaine and that σ receptor antagonists may be developed as pharmacotherapeutic agents for this application.