Characterization of a novel small chemical entity with anxiolytic- and antidepressant-like effects targeting multiple receptors

Abstract

Effective restoration of mental health in psychiatric disorders increasingly hinges on bridging neurobiological insights with clinically validated pharmacotherapies. The etiological heterogeneity of anxiety and depression underscores the need for novel compounds capable of modulating multiple neurochemical systems. In this study, we describe the synthesis and detailed characterization of a hydroxyl phenethyl acetamide analog (LQFM334) designed to target key receptors involved in mood regulation. LQFM334 exhibited a favorable safety profile and elicited robust anxiolytic- and antidepressant-like effects in mouse models. These behavioral outcomes were supported by in silico receptor profiling and in vitro functional assays, identifying LQFM334 as a potential agonist at serotonergic (5-HT1A/5-HT2A) and melatonergic (MT1/MT2) receptors. Pharmacological blockades of these receptors, but not of α-adrenergic or dopaminergic receptors, attenuated its behavioral effects. These findings position LQFM334 as a promising multireceptor ligand exemplifying a polypharmacology approach for the treatment of complex psychiatric conditions. The dual serotonergic and melatonergic mechanisms confer strong translational relevance involving the modulation of mood, stress resilience, and circadian rhythms domains that are frequently disrupted in affective disorders. These findings support LQFM334's potential in delivering broad-spectrum and clinically relevant psychiatric symptom relief.