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

项目总结 人们对迷幻药物兴趣的上升要求进一步探索其背后的机制 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。特别是，5-羟色胺受体5-HT1a是抗抑郁、抗焦虑、 以及抗精神病药物。5-HT1a也是多种致幻药物的高亲和力靶点，但它在 迷幻剂的生理作用一直被忽视，因为5-羟色胺受体5-HT2a被认为是 作为致幻效应的主要中介体。然而，精选的迷幻药拥有等同或更高的 对5-HT1A的亲和力强于5-HT2A。这个项目试图确定迷幻剂的独特分子细节 5-HT1a的结合和活性及其结构和功能研究。5-羟色胺-G-蛋白复合体的结构 结合迷幻和治疗药物将通过冷冻电子显微镜，揭示配体和 近原子分辨率下的换能器结合相互作用。这个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迷幻活性的水平信息。不同的信号通路 与其他G蛋白偶联受体的治疗或不良影响有关。因此， 现有迷幻剂在5-HT1a和5-HT2a的活性将通过两个主要信号来表征 途径-G蛋白和b-arrestin。此外，致幻的5-甲氧基二甲基色胺(5-MeO- DMT)对5-HT1a比5-HT2a有选择性。这个脚手架将被利用。一系列5-MEO-DMT 将合成和测试衍生物，以确定具有5-HT1a选择性的药效团。 5-HT2A型。这项实验将产生有助于描述5-HT1A在体内的作用的选择性化合物。在……里面 一组平行的实验，5-HT1a将被诱变，以确定在 5-HT1A的活性和信号转导。这些实验将证实结构观察，并确定重要的 5-HT1a配基结合口袋外的残基。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。总而言之， 拟议的研究将揭示5-HT1a和5-HT1a致幻活性的结构和化学决定因素 产生具有特定活性的新型迷幻化合物，可以在未来的研究中用于描绘 5-HT1A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.