Matsumoto R R, Hewett K L, Pouw B, Bowen W D, Husbands S M, Cao J J, Newman A H
Dept of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190, USA.
Neuropharmacology. 2001 Dec;41(7):878-86. doi: 10.1016/s0028-3908(01)00116-2.
Cocaine interacts with dopamine transporters and sigma 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 sigma receptors, were evaluated. The highly selective and potent sigma receptor ligand LR176 was used as a reference. Competition binding studies confirmed that the rank order of the compounds at dopamine transporters vs. sigma 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. sigma 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 sigma receptors, but not dopamine transporters. Although the rimcazole analogs were ineffective against the lethal effects of cocaine, the selective sigma receptor ligand LR176 provided significant protection. These data thus suggest that sigma receptors may mediate some of the toxic effects associated with cocaine and that sigma receptor antagonists may be developed as pharmacotherapeutic agents for this application.
可卡因在体内可达到的浓度下与多巴胺转运体和西格玛受体相互作用，这表明它们可能都是抗可卡因药物开发的可行靶点。利姆卡唑与这两个靶点都结合，并且还能减弱可卡因诱导的运动活性和致敏作用。为了进一步阐明利姆卡唑减弱可卡因诱导的惊厥和致死作用的潜在机制，对利姆卡唑和三种类似物（SH3/24、SH2/21、SH1/57）进行了评估，它们对多巴胺转运体和西格玛受体具有一系列不同的亲和力。高选择性且强效的西格玛受体配体LR176用作对照。竞争结合研究证实，这些化合物在多巴胺转运体与西格玛受体上的亲和力排序不同，从而能够将行为学研究中化合物的相对抗可卡因活性与其对多巴胺转运体和西格玛受体的亲和力进行关联。在行为学研究中，雄性瑞士韦伯斯特小鼠预先用其中一种化合物（0 - 60 mg/kg，腹腔注射）处理，然后在15分钟后用惊厥剂量（60 mg/kg，腹腔注射）或致死剂量（125 mg/kg，腹腔注射）的可卡因进行激发。当根据化合物的保护作用进行排序时，它们的抗惊厥作用与其对西格玛受体的亲和力之间存在显著相关性，但与多巴胺转运体的亲和力无关。尽管利姆卡唑类似物对可卡因的致死作用无效，但选择性西格玛受体配体LR176提供了显著的保护作用。因此，这些数据表明西格玛受体可能介导了一些与可卡因相关的毒性作用，并且西格玛受体拮抗剂可能被开发为用于此用途的药物治疗剂。
