BIOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF SIGMA RECEPTORS

该项目描述了生物化学和药理学特性， σ受体和配体。 发现σ受体调节 一种激动剂-拮抗剂方式的学习和记忆障碍， 作为至少三种不同受体系统的拮抗剂的药物： 美加明（烟碱乙酰胆碱受体），MK-801（NMDA/PCP 受体）和尼莫地平（L型钙通道）。 学习 使用Y-迷宫中的自发交替来评价能力 空间工作记忆测试，和步下被动回避， 长期记忆的水迷宫测试 PRE-084，选择性西格玛 在这个实验室发现的配体，衰减美加明，MK-801，和 尼莫地平诱导的记忆过程的损害在所有三个测试。 PRE-084的这些作用被σ受体拮抗剂拮抗 BMY-14802 利用在此合成的新σ受体配体， 实验室，DAPE（N-（2-[3，4-二氯苯基]乙基）-N-（6-氨基己基）- （2-[1-吡咯烷基]）乙胺），从大鼠中溶解的σ受体 肝膜通过亲和性被纯化近2,000倍， 层析 σ受体的进一步纯化正在进行中。

This project delineates biochemical and pharmacological properties of sigma receptors and ligands. Sigma receptors are found to modulate in an agonist-antagonist fashion learning and memory impairments induced by drugs acting as antagonists at least three different receptor systems: mecamylamine (the nicotinic acetylcholine receptor), MK-801 (the NMDA/PCP receptor), and nimodipine (the L-type calcium channel). Learning capacities are evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, and the step-down passive avoidance and the water-maze test for long-term memory. PRE-084, a selective sigma ligand discovered at this laboratory, attenuate mecamylamine, MK-801, and nimodipine-induced impairment of memory processes in all three tests. These effects of PRE-084 are antagonized by a sigma receptor antagonist BMY-14802. Utilizing a new sigma receptor ligand synthesized in this laboratory, DAPE (N-(2-[3,4-dichlorophenyl]ethyl)-N-(6-aminohexyl)- (2-[1-pyrrolidinyl])ethylamine), sigma receptors solubilized from rat liver membranes are purified to nearly 2,000-fold via an affinity chromatography. Further purification of the sigma receptors is underway.