Synthesis and Pharmacological Evaluation of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzodoxazol-2(3H)-one (SN79) a Cocaine Antagonist in Rodents

摘要

Cocaine interacts with monoamine transporters and sigma (σ) receptors, providing logical targets for medication development. In the present study, in vitro and in vivo pharmacological studies were conducted to characterize SN79, a novel compound which was evaluated for cocaine antagonist actions. Radioligand binding studies showed that SN79 had a nanomolar affinity for σ receptors and a notable affinity for 5-HT2 receptors, and monoamine transporters. It did not inhibit major cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP2C19, CYP2C9*1, CYP2D6, and CYP3A4, suggesting a low propensity for potential drug–drug interactions. Oral administration of SN79 reached peak in vivo concentrations after 1.5 h and exhibited a half-life of just over 7.5 h in male, Sprague–Dawley rats. Behavioral studies conducted in male, Swiss Webster mice, intraperitoneal or oral dosing with SN79 prior to a convulsive or locomotor stimulant dose of cocaine led to a significant attenuation of cocaine-induced convulsions and locomotor activity. However, SN79 produced sedation and motor incoordination on its own at higher doses, to which animals became tolerant with repeated administration. SN79 also significantly attenuated the development and expression of the sensitized response to repeated cocaine exposures. The ability of SN79 to significantly attenuate the acute and subchronic effects of cocaine provides a promising compound lead to the development of an effective pharmacotherapy against cocaine.Electronic supplementary materialThe online version of this article (doi:10.1208/s12248-011-9274-9) contains supplementary material, which is available to authorized users.