STUDIES ON SIGMA RECEPTORS AND THEIR LIGANDS

描述(改编自申请者摘要)：Sigma受体是 氟哌啶醇和其他抗精神病药物的高亲和力结合部位。 因为一些非典型的抗精神病药物被发现具有 对Sigma受体的高亲和力，已有研究提出Sigma 受体可能是新型抗精神病药物的共同作用部位 不产生锥体外系副作用的药物。其他 然而，研究人员提出，Sigma受体介导了 多巴胺能抗精神病药物的运动副作用。因为西格玛 受体是许多临床有用物质的主要结合部位。 精神药理药物，可能有必要阐明它们 结构和功能。一种29kD的多肽，已被鉴定为 Sigma受体与光亲和标记的结合亚单位 H|-叠氮化-DTG，现已通过十二烷基硫酸钠电泳法分离并逆转 相液相色谱。该多肽是从溶解的豚鼠中分离得到的。 猪肝细胞膜，含有浓度很高的Sigma 感受器。这项提案将尝试执行广泛的氨基酸 对分离出的蛋白质进行了序列分析。此外，还增加了 可能是西格玛受体复合体一部分的蛋白质(S)将被分离出来 通过使用几种新开发的亲和层析 层析矩阵。这项工作将提供一种在结构上 表征Sigma受体结合亚单位和/或附加蛋白 西格玛受体复合体。Sigma的结构表征 受体应该导致对该蛋白质功能的阐明， 因此，可能会导致更好地理解功能 精神药理药物与Sigma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.