Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants
Chemical Reviews – November 30, 2023
Source: OpenAlex
Summary
Psychedelics, including psilocybin and Lysergic acid diethylamide, are demonstrating significant promise in drug studies as rapid-acting antidepressants. These compounds influence behavior by engaging the serotonin 5-HT receptor. The core challenge in pharmacology is to refine their chemistry through chemical synthesis of novel alkaloids. This involves understanding functional selectivity at the 5-HT2A receptor to develop safer drugs that retain therapeutic benefits without hallucinogen effects. This Neurotransmitter Receptor Influence on Behavior research aims to unlock their full potential.
Abstract
Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure-activity relationships of existing 5-HT2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT2AR agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.