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Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activity.

ABSTRACT: NMDA (N-methyl-d-aspartate) receptor antagonists are promising tools for the treatment of a wide variety of central nervous system impairments including major depressive disorder. We present here the activity optimization process of a biphenyl-based NMDA negative allosteric modulator (NAM) guided by free energy calculations, which led to a 100 times activity improvement (IC50 = 50 nM) compared to a hit compound identified in virtual screening. Preliminary calculation results suggest a low affinity for the human ether-a-go-go-related gene ion channel (hERG), a high affinity for which was earlier one of the main obstacles for the development of first-generation NMDA-receptor negative allosteric modulators. The docking study and the molecular dynamics calculations suggest a completely different binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101.

SUBMITTER: Karlov DS 

PROVIDER: S-EPMC9298482 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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NMDA (<i>N</i>-methyl-d-aspartate) receptor antagonists are promising tools for the treatment of a wide variety of central nervous system impairments including major depressive disorder. We present here the activity optimization process of a biphenyl-based NMDA negative allosteric modulator (NAM) guided by free energy calculations, which led to a 100 times activity improvement (IC<sub>50</sub> = 50 nM) compared to a hit compound identified in virtual screening. Preliminary calculation results su  ...[more]

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