Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders^1,2,3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT_2A (ref. ⁴). However, 5-HT_1A 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-HT_1A is a validated therapeutic target^7,8, little is known about how psychedelics engage 5-HT_1A 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-HT_1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT_1A and 5-HT_2A enable the characterization of molecular determinants of 5-HT_1A 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-HT_1A agonists. We show that a 5-HT_1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT_1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

麦角酸二乙酰胺 (LSD) 和裸盖菇素等迷幻物质显示出治疗各种神经精神疾病的潜力^1,2,3。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介导其致幻和治疗作用（参考文献⁴）。然而，5-HT _1A也在色胺致幻剂的行为效应中发挥一定作用⁵，特别是 5-甲氧基-N,N-二甲基色胺 (5-MeO-DMT)，这是一种在科罗拉多河蟾蜍毒素中发现的致幻剂⁶。尽管 5-HT _1A是经过验证的治疗靶点^{7,8 ，但人们对致幻剂如何作用 5-HT} _1A以及该受体介导哪些作用知之甚少。在这里，我们通过 5-HT _1A的五种低温电子显微镜 (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。对 5-甲氧基色胺在 5-HT _1A和 5-HT _{2A上的结构-活性关系分析能够表征 5-HT 1A}信号传导效力、功效和选择性的分子决定因素。此外，我们还比较了 5-MeO-DMT 及其类似物与泛血清素激动剂 LSD 和临床使用的 5-HT _1A激动剂的结构相互作用和体外药理学。我们发现，5-HT _1A选择性 5-MeO-DMT 类似物在社交失败的动物中没有致幻作用，同时保留了抗焦虑和抗抑郁作用。我们的研究揭示了 5-HT _1A靶向致幻剂和疗法的分子方面，这可能有助于未来开发治疗神经精神疾病的新药物。