Structural studies of psychedelic activity at the serotonin receptor 5-HT1A

项目摘要 对迷幻药的兴趣的增加要求进一步探索迷幻药的潜在机制。 这些药物的治疗性质。5-羟色胺受体是公认的行为和 认知效应特别地，5-羟色胺受体5-HT 1A是抗抑郁药、抗焦虑药、 和抗精神病药物5-HT 1A也是多种迷幻药的高亲和力靶点，但它在 致幻剂的生理效应被忽视，因为5-羟色胺受体5-HT 2A被认为是 是致幻作用的主要媒介然而，精选的迷幻药具有同等或更高的 对5-HT 1A的亲和力超过5-HT 2A。该项目旨在确定迷幻药的独特分子细节， 结合和5-HT 1A的活性与结构和功能的研究。5-HT 1A-G-蛋白复合物的结构 结合到迷幻药和治疗药物将通过冷冻电子显微镜解决，揭示配体和 近原子分辨率的换能器结合相互作用。该项目还将解决缺乏受体的问题- 通过一系列体外功能研究获得有关迷幻活性的水平信息。不同的信号转导途径 与对其他G蛋白偶联受体的治疗或不良作用有关。因此，在本发明中， 现有致幻剂在5-HT 1A和5-HT 2A的活性将通过两个主要信号传导来表征 途径G蛋白和b抑制蛋白。此外，迷幻剂5-甲氧基-二甲基色胺（5-MeO- DMT）对5-HT 1A的选择性超过5-HT 2A。这个脚手架将被利用。一系列5-MeO-DMT 衍生物将被合成和测试，以确定药效团赋予5-HT 1A的选择性超过 5-HT 2A。该实验将产生可用于描述5-HT 1A在体内的作用的选择性化合物。在 在一组平行实验中，将对5-HT 1A进行诱变，以鉴定在以下方面发挥关键作用的单个残基： 5-HT 1A活性和信号传导。这些实验将证实结构观察，并确定重要的 5-HT 1A的配体结合口袋之外的残基。结构和功能的互补结果 实验将成为未来体内和药物设计工作的宝贵资源。总之， 拟议的研究将揭示5-HT 1A迷幻活性的结构和化学决定因素， 产生具有确定活性的新型迷幻化合物，可用于未来的研究， 5-HT 1A在迷幻生理学中的确切作用

PROJECT SUMMARY The rise of interest in psychedelic medicine calls for further exploration of the mechanisms underlying the therapeutic nature of these drugs. Serotonin receptors are well-established regulators of behavioral and cognitive effects. In particular, the serotonin receptor 5-HT1A is a primary target of antidepressant, anxiolytic, and antipsychotic medications. 5-HT1A is also a high-affinity target of multiple psychedelic drugs, but its role in the physiological effects of psychedelics has been overlooked as the serotonin receptor 5-HT2A is suggested to be the primary mediator of hallucinogenic effects. However, select psychedelics have equivalent or greater affinity for 5-HT1A over 5-HT2A. This project seeks to determine the unique molecular details of psychedelic binding and activity at 5-HT1A with structural and functional studies. Structures of a 5-HT1A-G-protein complex bound to psychedelic and therapeutic drugs will be solved via cryo-electron microscopy, revealing ligand and transducer binding interactions at near-atomic resolution. This project will also address the lack of receptor- level information on psychedelic activity with a series of in vitro functional studies. Distinct signaling pathways have been associated with therapeutic or undesirable effects at other G-protein coupled receptors. As such, the activity of existing psychedelics at 5-HT1A and 5-HT2A will be characterized across two major signaling pathways—G-protein and b-arrestin. Additionally, the psychedelic 5-methoxy-dimethyltryptamine (5-MeO- DMT) is reportedly selective for 5-HT1A over 5-HT2A. This scaffold will be exploited. A series of 5-MeO-DMT derivatives will be synthesized and tested to identify the pharmacophores conferring selectivity for 5-HT1A over 5-HT2A. This experiment will generate selective compounds useful for delineating the role of 5-HT1A in vivo. In a parallel set of experiments, 5-HT1A will be mutagenized to identify individual residues that play a key role in 5-HT1A activity and signaling. These experiments will confirm structural observations and identify important residues outside of 5-HT1A’s ligand binding pocket. The complementary results of structural and functional experiments will serve as an invaluable resource for future in vivo and drug-design efforts. In summary, the proposed studies will reveal the structural and chemical determinants of psychedelic activity at 5-HT1A and generate novel psychedelic compounds with defined activity, which can be used in future studies to delineate the precise role of 5-HT1A in psychedelic physiology.