Exploring Novel Antidepressants Targeting G Protein-Coupled Receptors and Key Membrane Receptors Based on Molecular Structures.

Major Depressive Disorder involves changes in signal transmission and brain structure. Progress in developing effective antidepressants has been slow due to the dominance of the monoamine hypothesis, and traditional drugs often have delayed effects, limited efficacy, and severe side effects. Recently, fast-acting compounds like S-ketamine and psychedelics such as LSD have emerged, prompting structural research on their target receptors. Cryo-electron microscopy has enabled high-resolution structures of the N-methyl-D-aspartate receptor and the 5-hydroxytryptamine 2A receptor, which can be used for virtual drug screening. The 5-HT1A receptor shows unique antidepressant effects in different brain regions, while AMPAR and TrkB receptors regulate synaptic plasticity. Using this structural information, highly selective antidepressants with rapid onset and fewer side effects have been designed.

Study at a glance

Abstract

Major Depressive Disorder (MDD) is a complex mental disorder that involves alterations in signal transmission across multiple scales and structural abnormalities. The development of effective antidepressants (ADs) has been hindered by the dominance of monoamine hypothesis, resulting in slow progress. Traditional ADs have undesirable traits like delayed onset of action, limited efficacy, and severe side effects. Recently, two categories of fast-acting antidepressant compounds have surfaced, dissociative anesthetics S-ketamine and its metabolites, as well as psychedelics such as lysergic acid diethylamide (LSD). This has led to structural research and drug development of the receptors that they target. This review provides breakthroughs and achievements in the structure of depression-related receptors and novel ADs based on these. Cryo-electron microscopy (cryo-EM) has enabled researchers to identify the structures of membrane receptors, including the N-methyl-D-aspartate receptor (NMDAR) and the 5-hydroxytryptamine 2A (5-HT2A) receptor. These high-resolution structures can be used for the development of novel ADs using virtual drug screening (VDS). Moreover, the unique antidepressant effects of 5-HT1A receptors in various brain regions, and the pivotal roles of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and tyrosine kinase receptor 2 (TrkB) in regulating synaptic plasticity, emphasize their potential as therapeutic targets. Using structural information, a series of highly selective ADs were designed based on the different role of receptors in MDD. These molecules have the favorable characteristics of rapid onset and low adverse drug reactions. This review offers researchers guidance and a methodological framework for the structure-based design of ADs.