Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

Abstract

Depression is one of the most prevalent mental diseases and a primary cause of disability worldwide with high incidence and high recurrence. The current deterioration of the COVID‐19 epidemic also pushes up the incidence of depression. Nevertheless, the currently available treatments remain inadequate response and limited efficacy. Therefore, discoveries of more potent and safer antidepressant drugs are urgently needed. In this review, the current potential physiological and pathological mechanisms of depression, and the clinical research progresses of candidate drugs as well as the recent advances in small‐molecule drug discovery for potential treatments of depression are systematically summarized. More importantly, the structure–activity relationships of compounds from different classes, the statistical analysis of the blood‐brain barrier permeability, the pharmacological targets, and the in vivo models are comprehensively discussed. Further insights on antidepressant drug discovery are also analyzed from multidimensional perspectives.

Functional consequences of a rare human serotonergic 5-HT1A receptor variant

“…5-HT receptors mediate many cellular processes ( Seyedabadi et al, 2014 ; Sharp and Barnes, 2020 ) and have been implicated in many brain disorders, including depression and anxiety ( Švob Štrac et al, 2016 ; Carhart-Harris and Nutt, 2017 ). 5-HT 1A receptor is the most abundant serotonin receptor and its ligands serve as pharmacological target for antidepressants and antipsychotic drug discovery ( Bantick et al, 2001 ; Newman-Tancredi, 2010 ; Powell et al, 2022 ; Yao et al, 2022 ). 5-HT 1A receptors regulate serotoninergic neurotransmission in serotoninergic neurons in the raphe nuclei where they serve as autoreceptors ( Lanfumey and Hamon, 2000 ).…”

Synthesis and biological evaluation of (+)-paeoveitol derivatives as novel antidepressants

“…More than 300 million people worldwide suffer from depression and the number is still increasing. Numerous antidepressants with different mechanisms have been approved and widely used in clinical treatment, mainly including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and specific serotonergic antidepressants (NaSSAs), and monoamine oxidase inhibitors (MAOIs) [ 2 ]. The approval of esketamine [ 3 ] and allopregnanolone [ 4 ] by the US Food and Drug Administration (FDA) for treatment-resistant depression and postpartum depression represents the most significant achievement in antidepressant drug development in the last three decades.…”