Journal Article

Structural pharmacology and therapeutic potential of 5-methoxytryptamines

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

2024

Overview

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. Detailed analyses of the serotonin receptor 5-HT 1A 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 5-Methoxytryptamine - analogs & derivatives / 5-Methoxytryptamine - chemistry / 5-Methoxytryptamine - pharmacology / 5-Methoxytryptamine - therapeutic use / 631/378/1831 / 631/378/340 / 631/535/1258/1259 / 631/92/436/2387 / 64/60 / 82/83 / 96/47 / 96/95 / 96/98 / Agonists / Animals / Anti-Anxiety Agents - chemistry / Anti-Anxiety Agents - pharmacology / Anti-Anxiety Agents - therapeutic use / Antidepressants / Antidepressive Agents - chemistry / Antidepressive Agents - pharmacology / Antidepressive Agents - therapeutic use / Anxiety / Anxiolytics / Cryoelectron Microscopy / Electron microscopy / Hallucinogens / Humanities and Social Sciences / Humans / LSD / Lysergic acid diethylamide / Lysergic Acid Diethylamide - chemistry / Lysergic Acid Diethylamide - pharmacology / Lysergide / Male / Methoxydimethyltryptamines - chemistry / Methoxydimethyltryptamines - pharmacology / Methoxydimethyltryptamines - therapeutic use / Mice / Models, Molecular / multidisciplinary / Mutagenesis / Pharmacology / Prescription drugs / Proteins / Psilocybin / Psychedelic drugs / Receptor, Serotonin, 5-HT1A - chemistry / Receptor, Serotonin, 5-HT1A - genetics / Receptor, Serotonin, 5-HT1A - metabolism / Receptor, Serotonin, 5-HT1A - ultrastructure / Receptor, Serotonin, 5-HT2A - chemistry / Receptor, Serotonin, 5-HT2A - genetics / Receptor, Serotonin, 5-HT2A - metabolism / Receptor, Serotonin, 5-HT2A - ultrastructure / Receptors / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Serotonin / Serotonin Receptor Agonists - chemistry / Serotonin Receptor Agonists - pharmacology / Serotonin Receptor Agonists - therapeutic use / Serotonin S1 receptors / Serotonin S2 receptors / Structure-Activity Relationship / Toxins / Tryptamine / Tryptamines