Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activity. Issue 7 (22nd June 2022)

• Record Type: Journal Article
• Authors: Karlov, Dmitry S.; Temnyakova, Nadezhda S.; Vasilenko, Dmitry A.; Barygin, Oleg I.; Dron, Mikhail Y.; Zhigulin, Arseniy S.; Averina, Elena B.; Grishin, Yuri K.; Grigoriev, Vladimir V.; Gabrel'yan, Alexey V.; Aniol, Viktor A.; Gulyaeva, Natalia V.; Osipenko, Sergey V.; Kostyukevich, Yury I.; Palyulin, Vladimir A.; Popov, Petr A.; Fedorov, Maxim V.
• Is Part Of: RSC medicinal chemistry. Volume 13:Issue 7(2022)
• Page Start: 822
• Page End: 830
• Publication Date: 2022-06-22
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d2md00001f
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : The activity of biphenyl-based NMDA receptor allosteric modulator identified in virtual screening (IC50 = 5 μM) was improved 100 times (IC50 = 50 nM); SAR is consistent with ifenprodil analogs. 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.