The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT2A serotonin receptor (5-HT2AR). Recent clinical studies have suggested that classical psychedelics may additionally have therapeutic potential for many neuropsychiatric conditions including depression, anxiety, migraine and cluster headaches, drug...
There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT2A serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound...
This brief review highlights some of the structure-activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines and certain tryptamines, which possess psychedelic activity in humans. Where they are known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of...
AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ 2 and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental...
Recently, psychedelics have emerged as promising therapeutics for numerous neuropsychiatric disorders. While their potential in the clinic has yet to be fully elucidated, understanding their molecular and biological mechanisms is imperative as these compounds are becoming widely used both in therapeutic and recreational contexts. This review examines the current understanding of basic biology,...
Over the past decade, psychedelic compounds have emerged as potentially transformative therapeutics for a variety of intractable neuropsychiatric conditions. However, historically most of the basic science has utilized these compounds as probes to interrogate various endogenous neurotransmitter systems-mainly the serotonin 5-HT2A receptor. With the renewed interest in utilizing these compounds...
Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT2A serotonin receptor (HTR2A), the 5-HT2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to...
-transducer-coupled structures of three representative isoforms (INI, VGV, and VSV) with the selective drug lorcaserin (Belviq) and the classic psychedelic psilocin. We also provide a comprehensive analysis of agonist activation and constitutive activity across all 24 protein isoforms. Collectively, these findings reveal a unique hydrogen-bonding network located on intracellular loop 2 that is...