An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones.
An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones.
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DOI：
10.1016/j.ejphar.2007.09.020
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发表时间：
2008-01
影响因子：
5
通讯作者：
Ivan Lee;Shiuhwei Chen;J. Schetz
中科院分区：
文献类型：
--
作者：
Ivan Lee;Shiuhwei Chen;J. Schetz
sigma1受体与多种药物结构类别相互作用的能力，加上其在体内的广泛分布，使其成为多种疾病的可能治疗靶点，从药物滥用到抑郁症再到阿尔茨海默病。令人惊讶的是，一些 sigma1 受体配体的报告亲和力值相差超过 50 倍。 sigma1 受体作为药物治疗靶点的潜力促使我们开发了一种明确的测定系统，用于测量配体与克隆的人 sigma1 受体的亲和力。在表征该系统并确定近三打化合物的真实亲和力值的过程中，发现一些多巴胺 D4 受体选择性化合物以高亲和力结合 sigma1 受体。对氟哌啶醇类化合物的系统分析揭示了临床相关丁酰苯之间清晰的结构亲和关系。抗抑郁药氟伏沙明、滥用药物甲基苯丙胺和神经类固醇黄体酮是众多配体之一，它们与 sigma1 受体的相互作用已通过我们的筛选测定得到证实。
The ability of the sigma1receptor to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma1receptor ligands vary more than 50-fold. The potential of the sigma1receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma1receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D4receptor selective compounds bind sigma1receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure–affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with the sigma1receptor were confirmed with our screening assay.