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

Abstract

Abstract. 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-HT 2 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.

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

“…CM764 binds sigma-2 receptors with ∼25-fold selectivity over sigma-1 receptors, with K i values of 3.5 6 0.9 nM at sigma-2 receptors and 86.6 6 2.8 nM at sigma-1 receptors. This is an increase in selectivity of 5-fold over the parent compound, SN79 (K i 5 7 and 27 nM at sigma-2 and sigma-1, respectively) (Kaushal et al, 2011).…”

“…In addition, there are also sigma-2 ligands that produce a calcium signal, but do not have the ability to kill cells. The sigma-2 receptor ligand, SN79 [6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl) butyl)benzo [d]oxazol-2(3H)-one] (Kaushal et al, 2011(Kaushal et al, , 2012 produces a small calcium signal in SK-N-SH neuroblastoma cells, but is unable to induce significant levels of cytotoxicity even at high doses (Garcia 2012). Based on such data we have proposed that the sigma-2 receptor may signal to pathways that bifurcate to those that result in apoptotic cell death and those that result in as yet uncharacterized nonapoptotic effects (Garcia and Bowen, 2010;Garcia 2012).…”

Blockade of Cocaine or Receptor Agonist Self Administration by Subtype-Selective Receptor Antagonists

“…That interval was based on in vivo metabolism studies available for several of the present compounds (Kaushal et al, 2011;James et al, 2012;Seminerio et al, 2012). The sR agonists studied were DTG, PRE-084, and (1)-pentazocine at doses specified in the figures.…”

“…The drugs used in this study and their sources were as follows: (2) Mach et al, 1999). AZ 66 (Seminerio et al, 2012), SN 79 (Kaushal et al, 2011), SN 167, CM 304 (James et al, 2012), CM 353, and CM 398 (Chu et al, 2015) were synthesized in the Division of Medicinal Chemistry, Department of BioMolecular Sciences, University of Mississippi School of Pharmacy (University, MS). Structures are shown in Fig.…”

“…The exception was DTG, which was initially dissolved in 1 N HCl, neutralized with 1 N NaOH, and diluted to the necessary concentration with water. Pretreatment times and doses of drugs used in this study were chosen based on published (Matsumoto, 2007;Kaushal et al, 2011) (Fig. 2, middle and bottom panels).…”