HALLUCINOGENS & 5-HT2A RECEPTORS: MECHANISMS AND EFFECTS

致幻剂

• 批准号: 6694029
• 负责人: HAREL WEINSTEIN
• 金额: $ 67.2万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6694029
• 关键词: hallucinogens; pharmacokinetics; psychopharmacology; receptor expression; serotonin receptor

Hallucinogens are drugs of abuse with an apparently unique mechanism of action producing disturbances in thought, perception and mood. The mechanisms for these actions of hallucinogens are unknown, but their association with 5-HT/2A receptor activities is longstanding. Despite considerable progress in characterizing behavioral, physiological and pharmacological properties of serotonergic hallucinogens, the molecular signature underlying the hallucinogenic potential remains elusive. The exact role of the 5-HT2A receptor in hallucinogenesis also remains obscure. To eliminate these important gaps in knowledge and understanding, this Program Project Grant (PPG) addresses a continuum of interrelated questions about function and effects elicits by hallucinogens on various mutant constructs of the human 5-HT/2A receptor (h5-HT2AR) expressed in cultured cells and in whole animals, in a common structural context of 3D receptor models and ligand structures. The fundamental molecular level of understanding sought here for the mechanisms of action of hallucinogens also aims to enable future efforts in structure/based design of therapeutic modalities against their abuse. The PPG is organized around comprehensive computation modeling, dynamics simulation, and structure analysis and design in Project 1. Functional probing for distinct mechanisms in the effects of hallucinogens on signal transduction, gene expression and behavior will be carried out in Projects 2&3 with pharmacological, biochemical and behavioral approaches involving genetically modified constructs in cell systems and whole mice. All three Projects will take the basis of specific structural hypotheses. Examples include one that equalizes the efficacies of 5-HT and hallucinogens (e.g., LSD), one that alters the interaction of the receptor with G proteins (e.g., coupling to small mw G proteins), and one that exhibits agonist-independent stimulation of second messenger production. Structure-activity considerations for distinctive models of interaction of hallucinogens with receptor models are also addressed in Project 1, and resulting interferences will inform choices of receptor constructs and ligands in protocols of the other Projects. The PPG will thus organize insights from multi-disciplinary experiments into a mechanistic understanding relating h5-HT/2AR actions of hallucinogens to a molecular basis for effects in the whole animal.

致幻剂是一种滥用药物，具有明显独特的作用机制，会扰乱思维、知觉和情绪。致幻剂的这些作用机制尚不清楚，但它们与 5-HT/2A 受体活性的关联由来已久。尽管在表征血清素致幻剂的行为、生理和药理学特性方面取得了相当大的进展，但其致幻潜力的分子特征仍然难以捉摸。 5-HT2A 受体在致幻作用中的确切作用仍然不清楚。为了消除这些知识和理解上的重要差距，该计划项目拨款 (PPG) 解决了一系列相互关联的问题，涉及致幻剂对在培养细胞和整个动物中表达的人类 5-HT/2A 受体 (h5-HT2AR) 的各种突变结构引起的功能和影响，在 3D 受体模型和配体结构的共同结构背景下。这里寻求对致幻剂作用机制的基本分子水平的理解也旨在使未来能够针对其滥用的治疗方式进行结构/基于设计的努力。项目 1 中的 PPG 围绕综合计算建模、动力学模拟以及结构分析和设计进行组织。项目 2 和 3 将采用药理学、生化和行为方法，涉及细胞系统和整个小鼠中的转基因结构，对致幻剂对信号转导、基因表达和行为的影响的不同机制进行功能探索。所有三个项目都将以具体的结构假设为基础。例子包括一种使 5-HT 和致幻剂（例如 LSD）功效相等的药物，一种改变受体与 G 蛋白相互作用的药物（例如与小分子量 G 蛋白偶联），以及一种对第二信使产生表现出不依赖激动剂的刺激的药物。项目 1 还讨论了致幻剂与受体模型相互作用的独特模型的结构-活性考虑因素，由此产生的干扰将为其他项目方案中受体构建体和配体的选择提供信息。因此，PPG 将把多学科实验的见解整理成一种机制理解，将致幻剂的 h5-HT/2AR 作用与对整个动物的影响的分子基础联系起来。