Structural pharmacology and therapeutic potential of 5-methoxytryptamines

This molecular study investigates the underpinnings of 5-MeO-DMT pharmacology and its therapeutic potential through cryogenic electron microscopy structures of 5-HT1A, medicinal chemistry, receptor mutagenesis, and mouse behaviour. The research characterizes molecular determinants of 5-HT1A signalling potency, efficacy, and selectivity, contrasting the structural interactions and pharmacology of 5-MeO-DMT with LSD and clinically used 5-HT1A agonists. Findings suggest a 5-HT1A-selective 5-MeO-DMT analogue devoid of hallucinogenic-like effects but with anxiolytic-like and antidepressant-like activity, potentially informing the development of new medications for neuropsychiatric disorders.

Abstract of 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 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 studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.”

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

Summary of Structural pharmacology and therapeutic potential of 5-methoxytryptamines