Discovery of Brain-Penetrative Negative Allosteric Modulators of NMDA Receptors Using FEP-Guided Structure Optimization and Membrane Permeability Prediction

N-Methyl-d-aspartate (NMDA) receptors,
a subtype of ionotropic glutamate receptors in the central nervous
system (CNS), have garnered attention for their role in brain disorders.
Specifically, GluN2A-containing NMDA receptors have emerged as a potential
therapeutic target for the treatment of depressive disorders and epilepsy.
However, the development of GluN2A-containing NMDA receptor-selective
antagonists, represented by N-(4-(2-benzoylhydrazine-1-carbonyl)benzyl)-3-chloro-4-fluorobenzenesulfonamide
(TCN-201) and its derivatives, faces a significant challenge due to
their limited ability to penetrate the blood–brain barrier
(BBB), hampering their in vivo characterization and
further advancement. In this study, we reported a series of 2-((5-(phemylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(cyclohexylmethyl)acetamide derivatives, achieved through
a structure-guided optimization strategy using free energy perturbation
(FEP) and BBB permeability estimation. Through systematic exploration
of various phenyl substitutions, compound 1f emerged
as a standout compound, demonstrating substantially enhanced inhibitory
activity compared with the lead compound TCN-213. Compound 1f not only displayed satisfactory BBB permeability but also showed
antidepressant-like potency in the hydrocortisone-induced zebrafish
depression-like model. All results position it as a promising candidate
for developing innovative therapeutics for NMDA receptor-related disorders.