DISTINCTIVE RECEPTOR ACTIONS IN HALLUCINOGEN MECHANISMS

产品说明：PPG的该组成项目的长期目标是在一定的细节水平上理解致幻药物滥用的分子作用机制，这将使得能够进行基于结构的设计和开发有效的干预治疗方法。因为它继续一个多学科的IRPG，拟议的工作利润从其结果产生的基本理解。重点是致幻剂的判别受体机制的计算建模和刺激。 它们与PPG紧密结合，在细胞中的相同系统上进行了新的实验工作，并在掺入相同受体结构的动物模型中对致幻剂的影响进行了研究，以解决将分子结构与对动物行为的影响联系起来的连续问题。该项目为探索和理解致幻剂的机制提供了结构背景，与实验探索直接相关，并基于共同的假设，即致幻潜力反映了负责配体-受体相互作用的不同分子机制的特定结构元素。因此，致幻剂的判别作用涉及1）它们在人5-HT 2A和5-HT 2C受体中的相互作用模型，从结合到参与活性状态稳定的受体的构象重排;和2）由于致幻剂的结合而引起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，一个重要的背景机制的理解和分子模型，以及一套合作协议测试成功正在进行的工作，基础的研究，旨在1：揭示不同的跨膜段7（TMS 7）结构的具体作用，在受体激活的动力学机制致幻剂; 2：完成一个迷幻剂不同作用的计算分析（与非致幻同类物相比）对由构成功能微域（FM）的所有结构基序（SM）引起的基于SM/FM的受体活化的影响;以及3：从计算实验中确定从扩展列表中绑定致幻剂的模式，并在结构上比较认知非致幻剂。所有研究的一个共同目标：将计算实验得出的结论转化为关于具有确定活性的受体构建体和配体的基于结构的假设，与差异反应（Sealfon组分）的发现相关，并考虑将其纳入该PPG的整个动物研究（母鸡组分）。

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.