DISTINCTIVE RECEPTOR ACTIONS IN HALLUCINOGEN MECHANISMS

描述：(申请人摘要)PPG的这个组成部分项目的长期目标是在详细的水平上了解致幻药物滥用的分子作用机制，从而能够基于结构/基础设计和开发有效的干预治疗方法。由于它延续了多学科的IRPG，拟议的工作受益于其成果产生的基本理解。重点是对致幻剂的辨别受体机制的计算建模和刺激。它们紧密地结合在PPG中，对细胞中的相同系统进行新的实验工作，并在动物模型中结合相同的受体结构来研究致幻剂的影响，以解决将分子结构与对动物行为的影响联系起来的一系列问题。该项目为探索和理解致幻剂的机制提供了一个结构背景，与实验探索直接相关，并基于一个共同的假设，即致幻潜力反映了负责不同分子机制的配体-受体相互作用的特定结构元素。因此，致幻剂的鉴别作用涉及1)它们在人5-HT2A和5-HT2C受体上的相互作用模型，从受体的结合到参与稳定活性状态的受体的构象重排；以及2)由于致幻剂结合而产生的任何这种独特的构象重排与G蛋白偶联的选择性和效率的关系。强大的最先进的方法、机制理解和分子模型的重要背景以及一套在正在进行的工作中成功测试的协作协议是这些研究的基础，这些研究旨在1：揭示各种跨膜片段7(TM 7)结构在致幻剂激活受体的动态机制中的具体作用；2：完成致幻剂(与非致幻同系物相比)对构成功能微域(FM)的所有结构基序(SM)对基于SM/FM的受体激活的差异影响的计算分析；以及3：从计算实验确定扩展列表中迷幻剂的结合模式，并从结构上比较非认知致幻剂。所有研究的共同目标：将计算实验得出的结论转化为基于结构的假设，即具有特定活性的受体结构和配体，与差异反应(Sealfon组分)的发现相关，并考虑将其纳入PPG的全动物研究(Hen组分)。

DESCRIPTION: (Applicant's Abstract) The long term goal of this component project of the PPG is to understand the molecular mechanisms of action of hallucinogenic drugs of abuse at a level of detail that will enable structure/based design and development of effective therapeutic methods of intervention. Because it continues a multi-disciplinary IRPG, , the proposed work profits from the fundamental understanding produced by its results. The focus is on computational modeling and stimulations of the discriminant receptor mechanisms of hallucinogens. They are integrated closely in the PPG with novel experimental work on the same systems in cells, and on the effects of hallucinogens in animal models incorporation the same receptor constructs, to address a continuum of questions connecting molecular structure with effects on animal behavior. The project provides a structural context for probing and understanding mechanisms of hallucinogens, in direct connection with experimental explorations and based on the common hypothesis that the hallucinogenic potential reflects specific structural elements responsible for distinct molecular mechanisms of ligand-receptor interaction. Hence,, the discriminant actions of hallucinogens addressed relate to 1) their models of interaction in human 5-HT2A and also 5-HT2C receptors, from binding to conformational rearrangements of the receptor that are involved in stabilization of the active status; and 2) the relation of any such distinctive conformational rearrangements due to the binding of hallucinogens to the selectivity and efficiency of G protein coupling. Powerful state-of-the-art approaches, a significant background of mechanistic understanding and molecular models, and a set of collaborative protocols tested successfully in ongoing work, underlies the studies aiming to 1: Reveal the specific role of various transmembrane segment 7 (TMS7) constructs in the dynamic mechanisms of receptor activation by hallucinogens; 2: Complete a computational analysis of differential effects of hallucinogens (compared to non-hallucinogenic congeners) on SM/FM based receptor activation by all structural motifs (SM) that constitute functional microdomains (FM); and 3: Determine from computational experiments the mode of binding of hallucinogens from an expanded list, and compare structurally cognitive non-hallucinogens. A common goal of all the studies: Translate conclusions reached from computational experiments into structure-based hypothesis about receptor constructs and ligands with defined activities, to correlate to findings on differential responses (Sealfon component) and to consider incorporation in whole animal studies (Hen component) of this PPG.