美国西奈山伊坎医学院Daniel Wacker等研究人员合作揭示5-甲氧基色胺的结构药理学和治疗潜力。相关论文于2024年5月8日在线发表在《自然》杂志上。

据研究人员介绍，麦角酸二乙基酰胺（LSD）和迷幻药等迷幻物质显示出治疗各种神经精神疾病的潜力。这些化合物被认为是通过血清素（5-羟色胺5-HT）受体5-HT_2A产生致幻和治疗效果的。不过，5-HT_1A也参与了色胺致幻剂的行为效应，特别是5-甲氧基-N,N-二甲基色胺（5-MeO-DMT），这是一种存在于科罗拉多河蟾蜍毒素中的迷幻剂。尽管5-HT_1A是一个有效的治疗靶点，但人们对迷幻药如何作用于5-HT_1A以及该受体介导了哪些效应知之甚少。

研究人员通过5-HT_1A的五种冷冻电镜（cryo-EM）结构、系统药物化学、受体诱变和小鼠行为，绘制了5-MeO-DMT药理学的分子基础。通过对5-HT_1A和5-HT_2A的5-甲氧基色胺进行结构-活性关系分析，可以确定5-HT_1A信号效力、功效和选择性的分子决定因素。此外，研究人员还对比了5-MeO-DMT及其类似物与泛羟色胺能激动剂LSD和临床常用的5-HT_1A激动剂的结构相互作用和体外药理学。研究表明，5-HT_1A选择性5-MeO-DMT类似物不具有致幻作用，但在社会挫败动物中仍具有抗焦虑和抗抑郁活性。该研究揭示了5-HT_1A靶向致幻剂和治疗药物的分子方面，这可能有助于未来开发治疗神经精神疾病的新药物。

附：英文原文

Title: Structural pharmacology and therapeutic potential of 5-methoxytryptamines

Author: Warren, Audrey L., Lankri, David, Cunningham, Michael J., Serrano, Inis C., Parise, Lyonna F., Kruegel, Andrew C., Duggan, Priscilla, Zilberg, Gregory, Capper, Michael J., Havel, Vaclav, Russo, Scott J., Sames, Dalibor, Wacker, Daniel

Issue&Volume: 2024-05-08

Abstract: Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1,2,3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens5, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads6. Although 5-HT1A is a validated therapeutic target7,8, little is known about how psychedelics engage 5-HT1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT1A agonists. We show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our stu

DOI: 10.1038/s41586-024-07403-2

Source: https://www.nature.com/articles/s41586-024-07403-2