Discovery of a fluorinated benzoxathiazine AMPA receptor PAM that stabilizes the GluA2 dimer interface and displays antidepressant-like effects.

Abstract

Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors hold significant therapeutic promise for neuropsychiatric disorders driven by synaptic dysfunction. Building upon our previously established oxathiazine-dioxide scaffold, we designed and synthesized a novel series of compounds through systematic exploration of the 6-position. Among these compounds, the fluorinated analog C17 was identified as a superior lead candidate. Advanced Gaussian accelerated molecular dynamics (GaMD) simulations demonstrated that C17 stabilizes the GluA2 ligand-binding domain (LBD) dimer more effectively than the clinical benchmark TAK-653. By establishing a robust hydrogen-bonding network, C17 acts as a "molecular glue" to tightly lock the receptor in its canonical activated conformation, thereby preventing transition into the desensitized state. Translating these mechanistic insights into in vivo activity, C17 exhibited potent antidepressant-like efficacy in a chronic social defeat stress mouse model. Electrophysiological characterization confirmed that C17 potentiates (S)-AMPA-induced currents in rat hippocampal neurons without intrinsic agonism. Furthermore, C17 concentration-dependently upregulated brain-derived neurotrophic factor (BDNF) expression. These results identify C17 as an AMPA receptor PAM with a distinct dimer-stabilizing profile, positioning it as a compelling candidate for treating major depressive disorder (MDD).