ORALLY ACTIVE AND SELECTIVE ENKEPHALIN PSEUDOPEPTIDES

口服活性和选择性脑啡肽假肽

• 批准号: 3210213
• 负责人: ARNO F SPATOLA
• 金额: $ 8.55万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3210213
• 关键词: amides; blood brain barrier; chemical structure function; conformation; cyclic compound; drug design /synthesis /production; dynorphins; enkephalins; neuropeptide receptor; opiate alkaloid; oxidation reduction reaction; peptides

Evidence has accumulated that postsynaptic serotonin (5-HT) receptors are an important site of action for hallucinogenic drugs. Concomitantly, there has been intensive study of 5-HT binding sites in brain and periphery. These sites have been classified into three main groups, most commonly referred to as 5-HT 1, 2 and 3. The 5-HT 1 sites have been further subdivided into 5-HT 1A, 1B, 1C and 1D. The overall goal of the present proposal is to characterize the electrophsiological actions of hallucinogens and related drugs mediated by 5-HT receptors postsynaptic to serotonergic raphe neurons. Hallucinogens to be tested include the ergot D-LSD, the indoles psilocin and N,N-dimeth-yltryptamine, and the phenylalkylamines mescaline and 2,5-dimethoxy-4-methylamphetamine. Their actions will be compared with those of presumably non-hallucinogenic agents including 5-HT, 5-carboxyamidotryptamine, lisuride, and 2-bromolysergic acid diethylamide. Modulation of excitatory actions of 5-HT by hallucinogens will also be investigated. Electrophysiological experiments (field potential recordings and both intracellular and extracellular unit studies) will be performed on the rat hippocampal slice in vitro. The actions of hallucinogens will be characterized in hippocampal field CA 1 and their electrophsiological effects compared with their potency and efficacy on the two 5-HT receptors linked to adenylate cyclase in membranes form rat hippocampus. The inhibition of adenylate cyclase will be assessed. LSD binds to all 5-HT 1 and 5-HT 2 sites. Regions of the hippocampal formation exhibiting the highest densities for 5-HT 1B, 5-HT 1C and 5-HT 2 sites will be examined to determine whether electophysiological effects can be linked to drug action at these sites. The possible linkage of the 5-HT 1B site to adenylate cyclase will be investigated. These studies should yield information on some serotonergic mechanisms of action of hallucinogens in the hippocampus and on the receptors and effectors through which their effects are mediated.

越来越多的证据表明突触后血清素 (5-HT) 受体 致幻药物的重要作用部位。 与此同时，还有 对大脑和外周的 5-HT 结合位点进行了深入研究。 这些站点被分为三个主要组，最常见的是 称为 5-HT 1、2 和 3。5-HT 1 位点已被进一步 细分为5-HT 1A、1B、1C和1D。 当前的总体目标 建议是描述电生理作用的特征 由突触后 5-HT 受体介导的致幻剂和相关药物 血清素能中缝神经元。 待测试的致幻剂包括麦角 D-LSD、吲哚赛洛辛和 N,N-二甲基色胺，以及 苯烷基胺麦司卡林和2,5-二甲氧基-4-甲基苯丙胺。 他们的 将与假定的非致幻剂的作用进行比较 包括 5-HT、5-羧酰胺色胺、麦角乙脲和 2-溴麦角酰 酸性二乙酰胺。 5-HT 兴奋作用的调节 致幻剂也将受到调查。 电生理实验 （场电位记录以及细胞内和细胞外单位 研究）将在体外对大鼠海马切片进行。 这 致幻剂的作用将在海马区 CA 1 中表征 以及它们的电生理效应与其效力的比较 对膜中与腺苷酸环化酶相关的两种 5-HT 受体的功效 形成大鼠海马体。 腺苷酸环化酶的抑制作用是 评估。 LSD 与所有 5-HT 1 和 5-HT 2 位点结合。 的地区 海马结构表现出最高密度的 5-HT 1B、5-HT 1C 和 5-HT 2 位点将被检查以确定电生理学是否 效果可能与这些位点的药物作用有关。 可能的联系 将研究 5-HT 1B 位点与腺苷酸环化酶的关系。 这些 研究应该提供一些血清素作用机制的信息 海马体中的致幻剂以及受体和效应器 它们的影响是通过它来调节的。