HALLUCINOGENS & 5-HT2A RECEPTORS: MECHANISMS AND EFFECTS

致幻剂

• 批准号: 6031964
• 负责人: HAREL WEINSTEIN
• 金额: $ 64.34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6031964
• 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，可引起思维、知觉和情绪障碍。致幻剂的这些作用的机制尚不清楚，但它们与5-HT/2A受体活性的关联是长期存在的。尽管在表征多巴胺能致幻剂的行为、生理和药理学特性方面取得了相当大的进展，但潜在的致幻潜力的分子特征仍然难以捉摸。5-HT 2A受体在幻觉发生中的确切作用也仍然不清楚。为了消除这些重要的知识和理解的差距，该计划项目资助（PPG）解决了一系列相互关联的问题，这些问题涉及致幻剂对培养细胞和整个动物中表达的人类5-HT/2A受体（h5-HT 2AR）的各种突变体结构的功能和影响，在3D受体模型和配体结构的共同结构背景下。在此寻求的对致幻剂作用机制的基本分子水平的理解也旨在使未来的努力能够在结构/基于设计的治疗方式中对抗其滥用。PPG围绕项目1中的综合计算建模、动力学仿真和结构分析与设计进行组织。致幻剂对信号转导，基因表达和行为的影响的不同机制的功能探测将在项目2和3中进行，涉及细胞系统和整个小鼠中的遗传修饰结构的药理学，生物化学和行为方法。所有三个项目都将以具体的结构假设为基础。实例包括使5-HT和致幻剂的功效相等的药物（例如，LSD），一种改变受体与G蛋白相互作用的药物（例如，偶联到小分子量G蛋白），和一种表现出激动剂非依赖性刺激第二信使产生。在项目1中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，并且所产生的干扰将在其他项目的方案中告知受体构建体和配体的选择。因此，PPG将从多学科实验中获得的见解组织成将致幻剂的h5-HT/2AR作用与整个动物中作用的分子基础相关的机械理解。