HALLUCINOGENS & 5-HT2A RECEPTORS: MECHANISMS AND EFFECTS

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、知觉和情绪紊乱。致幻剂的这些作用机制尚不清楚，但它们与5-HT/2A受体活性的关系是长期存在的。尽管在描述5 -羟色胺致幻剂的行为、生理和药理学特性方面取得了相当大的进展，但致幻潜力背后的分子特征仍然难以捉摸。5-HT2A受体在幻觉发生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空白，本计划项目资助（PPG）解决了一系列有关致幻剂对人类5-HT/2A受体（h5-HT2AR）在培养细胞和全动物中表达的各种突变结构的功能和影响的相关问题，在3D受体模型和配体结构的共同结构背景下。本文所寻求的对致幻剂作用机制的基本分子水平的理解，也旨在使今后在结构/基于设计的治疗方式方面的努力能够防止致幻剂的滥用。在项目1中，PPG围绕综合计算建模、动力学仿真和结构分析与设计进行组织。项目2和项目3将采用药理学、生化和行为学方法，对致幻剂对信号转导、基因表达和行为影响的不同机制进行功能探测，涉及细胞系统和全鼠的转基因构建。这三个项目都将以具体的结构假设为基础。例如，一种可以平衡5-羟色胺和致幻剂（如LSD）的功效，一种可以改变受体与G蛋白的相互作用（如与小分子量G蛋白偶联），一种可以表现出不依赖激动剂的第二信使产生刺激。在项目1中也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，由此产生的干扰将为其他项目协议中受体结构和配体的选择提供信息。因此，PPG将从多学科实验中组织见解，以了解致幻剂的h5-HT/2AR作用与整个动物效应的分子基础有关的机制。

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.