Pharmacokinetic Evaluation of a Novel Compound, Sn79, a Putative Sigma-2 Receptor Antagonist, By Intravenous and Oral Administration in Rats

Considering the alarming rates at which substance drug abuse, especially cocaine, is increasing in today\u27s society, there is a lot of impetus on the development of medications that can effectively help alleviate its toxicity and addiction. The affinity of cocaine to sigma receptors (sigma-1 and sigma-2) rendered the hypothesis that blocking sigma receptors could be a possible mechanism to attenuate cocaine-induced toxicity and addiction. In this view, SN79, a synthetic compound with selectivity to both sigma-1 and sigma-2 receptors garnered our attraction for its use as an antagonist. This dissertation encompasses detailed investigation of SN79 from drug discovery and development perspective. Development and validation of a bio-analytical method using ultra performance liquid chromatography-mass spectrophotometry to selectively separate and identify SN79 in biological matrix was a crucial part of this project. Determination of various physicochemical parameters including aqueous solubility, chemical stability, Log P and pKa etc are presented. A number of in vitro tests necessary for predicting the compound\u27s profile in the body were also performed. Single dose pharmacokinetic studies were conducted in fasted and fed state rats that help determine the disposition of SN79 in vivo

Synthesis and Pharmacological Evaluation of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a Cocaine Antagonist, in Rodents

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