Structural pharmacology and therapeutic potential of 5-methoxytryptamines

Psychedelics substances including LSD and psilocybin show great potential for the treatment of various neuropsychiatric disorders and are thought to mediate their hallucinogenic and therapeutic effects via the 5-HT2A serotonin receptor. However, 5-HT1A also appears to play a role in the behavioral effects of tryptamine hallucinogens, particularly 5-MeO-DMT, a psychedelic found in Colorado River toad toxin6. Although 5-HT1A is a validated therapeutic target, 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 via five 5-HT1A cryoEM structures, systematic medicinal chemistry, mutational studies, and mouse behavior. Through structure-activity relationship (SAR) studies of 5-methoxytryptamines at both 5-HT1A and 5-HT2A, including structure-guided receptor mutagenesis and ligand modifications, we characterize molecular determinants of 5-HT1A signaling potency, efficacy, and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogs to the pan-serotonergic agonist LSD and clinically used 5-HT1A agonists. We show that a 5-HT1A-selective 5-MeO-DMT analog 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, empowering future development of novel medications for neuropsychiatric disorders.