Identification of a Class of Novel, Selective, Structurally Distinct GluN2A Negative Allosteric Modulators Through...

GluN2A containing N-methyl-D-aspartate receptors are involved in neuropsychiatric disorders. Studies with GluN2A knockout mice revealed an anxiolytic and antidepressant-like phenotype across multiple behavioral tests and in humans. Despite its relevance, the development of selective GluN2A antagonists has been hindered by challenges in achieving compound specificity and favorable pharmacological profiles. While competitive antagonists show GluN2A preference, negative allosteric modulators like TCN-201 offer superior selectivity but suffer from poor solubility and glycine sensitivity. Subsequent analogues such as MPX-007 showed significant improvements in potency but remained unsuitable for in vivo use due to their efflux liability, associated with the presence of a sulfonamide moiety as an important pharmacophoric feature. Herein, we report a structurally distinct novel class of GluN2A-selective negative allosteric modulators identified through virtual screening of the MPX-007 binding site and advanced in vitro profile, with an optimized compound 6m, representing a promising and structurally unique tool for advancing mechanistic studies and exploring therapeutic potential targeting GluN2A.