Structural pharmacology and therapeutic potential of 5-methoxytryptamines.
Abstract
Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders<sup>1-3</sup>. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT<sub>2A</sub> (ref. <sup>4</sup>). However, 5-HT<sub>1A</sub> also plays a part in the behavioural effects of tryptamine hallucinogens<sup>5</sup>, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads<sup>6</sup>. Although 5-HT<sub>1A</sub> is a validated therapeutic target<sup>7,8</sup>, little is known about how psychedelics engage 5-HT<sub>1A</sub> 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<sub>1A</sub>, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> enable the characterization of molecular determinants of 5-HT<sub>1A</sub> 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<sub>1A</sub> agonists. We show that a 5-HT<sub>1A</sub>-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<sub>1A</sub>-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.
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