NOVEL NICOTINIC RECEPTOR MEDIATED THERAPEUTIC AGENTS

新型烟碱受体介导的治疗剂

• 批准号: 6378925
• 负责人: Mark L. Trudell
• 金额: $ 28.55万
• 依托单位: UNIVERSITY OF NEW ORLEANS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378925
• 关键词: analgesia; chemical structure; chemical synthesis; dopamine; drug abuse chemotherapy; drug addiction antagonist; drug design /synthesis /production; injection /infusion; laboratory mouse; laboratory rat; molecular shape; neurotransmitter transport; nicotine; nicotinic receptors; norepinephrine; receptor binding; tobacco abuse

The objective of the proposed multidisciplinary, multiuniversity research initiative is the development of nicotine acetylcholine receptor (nAChR) selective agonists and antagonists as potential therapeutic agents for nicotine addiction and other central nervous system disorders mediated by nAChRs. Novel analogues of the potent nAChR ligand, epibatidine will be synthesized and evaluated in vitro and in vivo as potential potent selective nAChR ligands. The specific aims of the proposed work to achieve this objective are fourfold: 1) The efficient syntheses of (q)-epibatidine as well as natural (-)-epibatidine and (+)- epibatidine will be investigated to provide useful quantities of these rare compounds for study. In addition, useful enantiomeric intermediates will be generated from this study for use in concurrent structure activity relationship studies. 2) Novel analogues of epibatidine and hybrid molecules of epibatidine and potent nAChR ligands will be synthesized and tested in in vitro paradigms to systematically investigate the structural features associated with the molecular recognition by nAChRs in the brain. In addition, epibatidine and related-analogues will be evaluated at brain opioid receptors to establish receptor selective binding and clearly establish nAChR selectivity. 3) Novel analogues of epibatidine will be tested for functional agonist/antagonist activity at nAChR. This will be done by measuring the effects of these compounds on dopamine and norepinephrine release. 4) Selected potent active analogues will be employed in in vivo studies to investigate nAChR mediated analgesia to establish agonist or antagonist activity. Both central and peripheral nervous L system activity will be evaluated.

拟议的多学科多工资研究计划的目的是发展烟碱乙酰胆碱受体（NACHR）选择性激动剂和拮抗剂，作为尼古丁成瘾和其他由NACHRS介导的尼古丁成瘾和其他中枢神经系统疾病的潜在治疗剂。 有效的NACHR配体的新型类似物，Epibatidine将在体外和体内合成和评估为潜在的有效选择性NACHR配体。 提出的工作实现此目标的具体目的是四重：1）（q） - pepibatidine以及天然（ - ） - epibibatidine和（+） - epibibatidine的有效合成，以提供这些稀有化合物的有用数量。 此外，本研究将生成有用的对映体中间体，以用于并发结构活动关系研究。 2）将在体外范式中合成并测试表皮定和有效的NACHR配体的表皮和杂种分子的新型类似物，以系统地研究与大脑中NACHRS的分子识别相关的结构特征。此外，将在脑阿片类受体上评估表皮定和相关的分析，以建立受体选择性结合并明确建立NACHR选择性。 3）Epibatidine的新型类似物将测试NACHR的功能激动剂/拮抗剂活性。 这将通过测量这些化合物对多巴胺和去甲肾上腺素释放的影响来完成。 4）选定的有效的活性类似物将用于体内研究中，以研究NACHR介导的镇痛作用以建立激动剂或拮抗剂活性。 将评估中央和周围神经L系统活性。