Structural pharmacology and therapeutic potential of 5-methoxytryptamines

• 成果类型: Article
• 署名作者: 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
• 署名单位: Icahn School of Medicine at Mount Sinai; Columbia University; Icahn School of Medicine at Mount Sinai; Columbia University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5164
• DOI: 10.1038/s41586-024-07403-2
• 发表日期: 2024-05-23
• 关键词: social defeat stress; crystal-structure; serotonin; 5-ht1a; receptors; hallucinogen; psilocybin; ketamine; features

摘要

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1-3. 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 studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders. Detailed analyses of the serotonin receptor 5-HT1A and the psychedelic 5-methoxy-N,N-dimethyltryptamine reveal the differences in receptor structural pharmacology that mediate signalling specificity, efficacy and potency, findings that may facilitate the development of new neuropsychiatric therapeutics.