Structural pharmacology and therapeutic potential of 5-methoxytryptamines.

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders ^1-3 . 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 hallucinogens ⁵ , particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads ⁶ . 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)