Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia 26506, USA.
J Pharmacol Exp Ther. 2010 May;333(2):491-500. doi: 10.1124/jpet.109.161398. Epub 2010 Jan 25.
Cocaine is a highly abused drug without effective pharmacotherapies to treat it. It interacts with sigma (sigma) receptors, providing logical targets for the development of medications to counteract its actions. Cocaine causes toxic and stimulant effects that can be categorized as acute effects such as convulsions and locomotor hyperactivity and subchronic effects including sensitization and place conditioning. In the present study, 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione (CM156), a novel compound, was developed and tested for interactions with sigma receptors using radioligand binding studies. It was also evaluated against cocaine-induced effects in behavioral studies. The results showed that CM156 has nanomolar affinities for each of the sigma receptor subtypes in the brain and much weaker affinities for non-sigma binding sites. Pretreatment of male Swiss-Webster mice with CM156, before administering either a convulsive or locomotor stimulant dose of cocaine, led to a significant attenuation of these acute effects. CM156 also significantly reduced the expression of behavioral sensitization and place conditioning evoked by subchronic exposure to cocaine. The protective effects of CM156 are consistent with sigma receptor-mediated actions. Together with previously reported findings, the data from CM156 and related sigma compounds indicate that sigma receptors can be targeted to alleviate deleterious actions of cocaine.
可卡因是一种高度滥用的药物，目前尚无有效的药物治疗方法。它与西格玛（sigma）受体相互作用，为开发对抗其作用的药物提供了合理的靶点。可卡因会引起毒性和兴奋作用，这些作用可以分为急性作用，如惊厥和运动过度兴奋，以及亚慢性作用，包括敏化和位置条件反射。在本研究中，开发了一种新型化合物 3-(4-(4-环己基哌嗪-1-基)丁基)苯并[d]噻唑-2(3H)-硫酮（CM156），并使用放射性配体结合研究测试了其与西格玛受体的相互作用。还在行为研究中评估了其对可卡因诱导作用的影响。结果表明，CM156 对大脑中每种 sigma 受体亚型均具有纳摩尔亲和力，而对非 sigma 结合位点的亲和力较弱。在给予可卡因致惊厥或运动兴奋剂剂量之前，用 CM156 预处理雄性瑞士-韦伯斯特小鼠，可显著减弱这些急性作用。CM156 还显著降低了亚慢性暴露于可卡因引起的行为敏化和位置条件反射的表达。CM156 的保护作用与 sigma 受体介导的作用一致。与之前的报道结果一致，CM156 和相关 sigma 化合物的数据表明，sigma 受体可以作为靶点，减轻可卡因的有害作用。
