STUDIES ON SIGMA RECEPTORS AND THEIR LIGANDS

描述（改编自申请人的摘要）： 氟哌啶醇和其他抗精神病药物的高亲和力结合位点。 因为一些非典型抗精神病药物已被发现有一个 对σ受体具有高亲和力，已经提出σ 受体可能是新型抗精神病药的共同作用部位 不产生锥体外系副作用的药物。 其他 然而，研究者提出σ受体介导了 多巴胺能抗精神病药物的运动副作用。 因为sigma 受体是许多临床上有用的 精神药理学药物，这可能是必要的，以阐明其 结构和功能。 一种29 kD多肽，已被鉴定为 具有光亲和标记的σ受体的结合亚基 \H|- 叠氮基-DTG，现已通过SDS-电泳分离并逆转录 相HPLC。 这种多肽已从溶解的豚鼠中分离出来， 猪肝膜，其含有非常高浓度的西格玛 受体。 该提案将尝试执行广泛的氨基酸 对分离的蛋白质进行序列分析。 此外，额外的 分离可能是σ受体复合物一部分的蛋白质 通过使用几种新开发的亲和色谱法， 色谱基质。 这项工作将提供一种手段， 表征σ受体结合亚基和/或另外的蛋白质 sigma受体复合物的一部分 sigma的结构表征 受体的研究将有助于阐明这种蛋白质的功能， 因此，可能会导致对功能的更好理解 精神药物与西格玛结合的后果 大脑和其他组织中的受体。

DESCRIPTION (Adapted from the Applicant's Abstract): Sigma receptors are high affinity binding sites for haloperidol and other antipsychotic drugs. Because a number of atypical antipsychotic agents have been found to have a high affinity for sigma receptors, it has been proposed that sigma receptors may represent a common site of action for novel antipsychotic drugs which do not produce extrapyramidal side-effects. Other investigators, however, have proposed that sigma receptors mediate the motor side-effects of dopaminergic antipsychotic agents. Because sigma receptors are the major binding sites for many clinically useful psychopharmacological agents, it may be essential to elucidate their structure and function. A 29kD polypeptide, that has been identified as the binding subunit of the sigma receptor with the photoaffinity label \H|-azido-DTG, has now been isolated by SDS-electrophoresis and reversed phase HPLC. This polypeptide has been isolated from the solubilized guinea pig liver membrane, which contains a very high concentration of sigma receptors. This proposal will attempt to perform extensive amino acid sequence analysis on the isolated protein. Furthermore, additional protein(s) that may be part of the sigma receptor complex will be isolated by affinity chromatography using several newly developed affinity chromatography matrices. This work will provide a means to structurally characterize the sigma receptor binding subunit and/or additional proteins of the sigma receptor complex. Structural characterization of the sigma receptor should result in an elucidation of the function of this protein, and, therefore, may lead to a greater understanding of the functional consequences of the binding of psychopharmacological agents to sigma receptors in the brain and other tissues.