STEREOCHEMICAL ASPECTS OF HALLUCINOGENESIS

致幻剂的立体化学方面

• 批准号: 3207155
• 负责人: DAVID E NICHOLS
• 金额: $ 13.16万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207155
• 关键词: X ray crystallography; amphetamines; autoradiography; behavioral medicine; brain metabolism; caudate nucleus; chemical stimulation; chemical synthesis; dopamine receptor; drug metabolism; drug receptors; hippocampus; indoles; inositol phosphates; isomer; laboratory rat; lysergic acid diethylamide; phenylethylamines; psychotomimetic drug; sensory discrimination; serotonin receptor; stereochemistry; tryptamines

This proposal outlines the synthesis and evaluation of a variety of isomers and bioisosteres of hallucinogen analogues. All these represent chemical structures where the conformational flexibility or stereochemistry has been fixed, so that analysis of structure- activity relationships will be facilitated. Particular compounds of interest to be examined include lysergic acid amides of the isomers of 2,4-dimethylazetidine and 2,5-dimethylpyrrolidine, substituted trans-indol-3-ylcyclopropylamine and certain benzofuran and 2,3-dihydrobenzofuran bioisosteres of the hallucinogenic tryptamines and amphetamines. Receptor binding profiles will be examined for each of the series, for affinity at a variety of serotonin receptor subtypes, and for the lysergic acid amides at dopamine D-l and D-2 receptors. Ability to stimulate inositol triphosphate turnover will be used to assess agonist/antagonist activity in the series. The two-lever drug discrimination paradigm will be used as a measure of in vivo hallucinogen potency, utilizing rats trained to discriminate saline from LSD. Other training drugs may be used in this paradigm, where appropriate, as in vivo correlates to observed in vivo results. Molecular mechanics procedures will be used to model the conformational mobility and preferred conformations in these series.

该提案概述了一种多样性的综合和评估 幻觉类似物的异构体和生物蛋白酶。 所有这些 表示构象柔韧性的化学结构 或立体化学已固定，因此结构分析 - 活动关系将得到促进。 特定化合物 值得研究的值包括 2,4-二甲基辛丁和2,5-二甲基吡咯烷酮的异构体， 取代的trans-indol-3-基环丙丙酰胺和某些苯并呋喃 和2,3二氢苯并呋喃的生物蛋白酶 色素和苯丙胺。 受体结合轮廓将是 检查了该系列的每个系列，以相关性 5-羟色胺受体亚型，对于脂肪酸酰胺 多巴胺D-L和D-2受体。 刺激肌醇的能力 三磷酸化周转率将用于评估激动剂/拮抗剂 该系列的活动。 两级药物歧视范式 将用作体内幻觉效力的量度 利用受过训练的大鼠将盐水与LSD区分开。 其他 在适当的情况下，可以在此范式中使用培训药物 体内与观察到的体内结果相关。 分子 力学程序将用于建模构象 在这些系列中的移动性和首选构象。