σ受体配体BD1008的新型类似物可减轻可卡因对小鼠的毒性作用。

Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-induced toxicity in mice.

作者信息

Matsumoto Rae R, Gilmore Deborah L, Pouw Buddy, Bowen Wayne D, Williams Wanda, Kausar Amina, Coop Andrew

机构信息

Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, P.O. Box 26901, CPB 337 Oklahoma City, OK 73190, USA.

出版信息

Eur J Pharmacol. 2004 May 10;492(1):21-6. doi: 10.1016/j.ejphar.2004.03.037.

DOI:10.1016/j.ejphar.2004.03.037

PMID:15145701

Abstract

Previous studies have shown that BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and related analogs attenuate the toxicity and stimulant effects of cocaine through antagonism of sigma receptors. In the present study, six analogs of BD1008 (UMB 98-103) were synthesized and evaluated in receptor binding and behavioral studies. Competition binding studies confirmed that all six compounds have high affinity for sigma1 receptors, moderate affinity for sigma2 receptors, and low to negligible affinity for monoamine transporters, opioid, N-methyl-D-aspartate, dopamine, and 5-HT receptors. In behavioral pharmacological studies, pretreatment of mice with UMB 100, UMB 101, or UMB 103 significantly attenuated cocaine-induced convulsions and lethality. Together with earlier studies, the data suggest that analogs of BD1008 are promising medication development leads for reducing the toxicity of cocaine.

摘要

先前的研究表明，BD1008（N-[2-(3,4-二氯苯基)乙基]-N-甲基-2-(1-吡咯烷基)乙胺）及相关类似物通过拮抗σ受体来减轻可卡因的毒性和兴奋作用。在本研究中，合成了BD1008的六种类似物（UMB 98 - 103），并在受体结合和行为学研究中进行了评估。竞争结合研究证实，所有六种化合物对σ1受体具有高亲和力，对σ2受体具有中等亲和力，对单胺转运体、阿片类、N-甲基-D-天冬氨酸、多巴胺和5-羟色胺受体的亲和力低至可忽略不计。在行为药理学研究中，用UMB 100、UMB 101或UMB 103对小鼠进行预处理可显著减轻可卡因诱导的惊厥和致死率。与早期研究一起，这些数据表明BD1008的类似物是减少可卡因毒性的有前景的药物开发先导物。