RECEPTOR DETERMINANTS OF HALLUCINOGEN ACTIONS

虽然滥用致幻药物被认为会产生 通过与5-HT 2/5-HT 1C亚型相互作用产生的精神作用 受体，这种相互作用的标志，这是特定于他们的 独特的神经心理作用是未知的。最近的隔离 代表5-HT 2、5-HT 1C和其它高表达的多个cDNA克隆 亲合性致幻剂结合位点允许的特性和基础 在分子水平上探索致幻剂与受体的相互作用。 两个相关但不同的假设是一致的， 实验数据对精神影响至关重要的参数 5-HT配体可能涉及它们的结合位点、活化和功能的差异。 或偶联特异性。或者， 致幻剂可能部分来自于它们与其中一种物质的相互作用。 新发现的与致幻剂高度结合的受体。到 检查这些假设，我们建议整合分子生物学， 计算分子建模（这个互动的温斯坦组件 研究项目补助金-IRPG）和药理学方法（Maayani 成分），以探索致幻剂作用的基础。 具体 参与致幻剂与5-HT 2和5-HT 1C结合的残基 将对受体进行研究。选择用于突变的残基将是 基于已知对其他GPCR至关重要的残基， 考虑和假设来自分子建模。的 配体结合和受体结合差异的结构基础 5-HT 2和5-HT 1C受体之间的激活/效应物偶联将 通过每一个的协调突变来研究。的空间和 将探讨跨膜螺旋的功能关系， 验证正在进行的建模（Weinstein组件），从而使 关于致幻剂相互作用部位的更精确的假设 开发和测试。其他5-HT亚型正在鉴定中 通过分子克隆，我们的研究将扩展到其他领域。 人类受体作为特别引人注目的靶点出现， 致幻剂受体突变体与精神药物的协同研究 和非精神病配体将有助于澄清的分子基础， 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影响。

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.