RECEPTOR DETERMINANTS OF HALLUCINOGEN ACTIONS

虽然滥用致幻药物被认为会产生他们的 它们与5-HT2/5-HT1C亚型相互作用的精神药物效应 受体，这种相互作用的标志是其特有的 独特的神经心理行为是未知的。最近被孤立的 多个代表5-HT2、5-HT1C和其他高密度脂蛋白的cDNA克隆 致幻剂亲和力结合部位允许的特点和依据 迷幻剂-受体的相互作用有待在分子水平上进行探索。 两个相关但截然不同的假设与目前一致 实验数据。对精神药物效应至关重要的参数 5-羟色胺配体可能涉及其结合部位、激活方式的差异 或耦合的专一性。或者，精神药物的作用 迷幻剂可能部分来源于它们与一种 新发现的受体能以高亲和力结合致幻剂。至 检验这些假设，我们建议将分子生物学、 计算分子建模(本互动的Weinstein组件 研究项目Grant-IRPG)和药理学方法(Maayani 成分)探讨致幻剂作用的基础。具体的 致幻剂与5-HT2和5-HT1C结合的残基 我们将探索受体。选择进行突变的残基将是 基于已知对其他GPCR至关重要的残留物，经验性的 从分子模拟中得出的考虑因素和假设。这个 配体结合和受体差异的结构基础 5-HT2和5-HT1C受体之间的激活/效应偶联将 通过每种基因的协同突变进行研究。空间和 将探讨跨膜螺旋的功能关系 验证正在进行的建模(Weinstein组件)，从而实现 关于迷幻剂相互作用部位的更精确假设 开发和测试。其他5-羟色胺亚型正在确定中 通过分子克隆快速进行，我们的研究将扩展到其他 人类受体成为特别引人注目的靶标 迷幻剂。受体突变与精神药物的协同研究 和非精神药物配体将有助于阐明分子基础 这些化学物质的作用，并可能提出新的治疗方法 调节这些滥用药物的效果。

While hallucinogenic drugs of abuse are believed to generate their psychotropic effects through their interaction with 5-HT2/5-HT1C subtype receptors, the hallmark of this interaction which is specific to their unique neuropsychological actions is unknown. The recent isolation of multiple cDNA clones representing the 5-HT2, 5-HT1C and other high affinity hallucinogen binding sites allows the characteristics and basis of hallucinogen-receptor interactions to be probed at the molecular level. Two related but distinct hypotheses are consistent with present experimental data. The parameters critical to the psychotropic effects of 5-HT ligands might involve differences in their binding site, activation or coupling specificity. Alternatively, the psychotropic effects of hallucinogens may derive, in part, from their interaction with one of the newly described receptors which bind hallucinogens with high affinity. To examine these hypotheses, we propose to integrate molecular biological, computational molecular modeling (Weinstein component of this Interactive Research Project Grant-IRPG) and pharmacological approaches (Maayani component) to probe the basis of hallucinogen action. The specific residues involved in the binding of hallucinogens to the 5-HT2 and 5-HT1C receptors will be explored. The residues selected for mutation will be based upon residues known to be critical for other GPCRs, empirical considerations and hypotheses derived from molecular modeling. The structural basis for the differences in ligand binding and receptor activation/effector coupling between the 5-HT2 and 5-HT1C receptors will be investigated by coordinated mutation of each. The spatial and functional relationships of the transmembrane helices will be probed to validate the ongoing modeling (Weinstein component) and thereby to enable more precise hypotheses about the sites of hallucinogen interaction to be developed and tested. Additional 5-HT subtypes are being identified rapidly via molecular cloning and our studies will be extended to other human receptors which emerge as particularly compelling targets of hallucinogens. The coordinated study of receptor mutants with psychotropic and non psychotropic ligands will help clarify the molecular basis of the actions of these chemicals and may suggest novel therapeutic approaches to modulate the effect of these drugs of abuse.