DISTINCTIVE RECEPTOR ACTIONS IN HALLUCINOGEN MECHANISMS

描述：（申请人摘要）PPG的这个组成项目的长期目标是了解致幻药物滥用的分子机制，这将使基于结构的设计和开发有效的治疗干预方法成为可能。因为它是一个多学科的IRPG，所以建议的工作受益于其结果产生的基本理解。重点是计算模型和幻觉剂的区别受体机制的刺激。在PPG中，它们与新的实验工作紧密结合在一起，这些实验工作涉及细胞中相同的系统，以及含有相同受体结构的致幻剂在动物模型中的作用，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，并基于常见的假设，即致幻剂的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，致幻剂的鉴别作用与1)它们在人类5-HT2A和5-HT2C受体中的相互作用模型有关，从结合到受体的构象重排，这些受体参与了活性状态的稳定；2)致幻剂与G蛋白偶联的选择性和效率之间的特殊构象重排关系。强大的先进方法，重要的机制理解背景和分子模型，以及一系列在正在进行的工作中成功测试的协作方案，奠定了以下研究的基础：1 .揭示各种跨膜片段7 （TMS7）构建物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（与非致幻剂同族物相比）对构成功能微域（FM）的所有结构基序（SM）的SM/FM受体激活的差异效应的计算分析；和3：从计算实验中确定从扩展列表中的致幻剂的结合模式，并比较结构上认知的非致幻剂。所有研究的共同目标是：将计算实验得出的结论转化为关于具有确定活性的受体结构和配体的基于结构的假设，与差异反应（Sealfon成分）的发现相关联，并考虑将该PPG纳入全动物研究（Hen成分）。

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.