| Literature DB >> 28105280 |
Elisia Villemure1, Matthew Volgraf1, Yu Jiang2, Guosheng Wu2, Cuong Q Ly1, Po-Wai Yuen2, Aijun Lu2, Xifeng Luo2, Mingcui Liu2, Shun Zhang2, Patrick J Lupardus1, Heidi J A Wallweber1, Bianca M Liederer1, Gauri Deshmukh1, Emile Plise1, Suzanne Tay1, Tzu-Ming Wang1, Jesse E Hanson1, David H Hackos1, Kimberly Scearce-Levie1, Jacob B Schwarz1, Benjamin D Sellers1.
Abstract
The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723. GNE-5729 (13), a pyridopyrimidinone-based NMDAR PAM, was identified with both an improved pharmacokinetic profile and increased selectivity against AMPARs. We also include X-ray structure analysis and modeling to propose hypotheses for the activity and selectivity differences.Entities:
Keywords: AMPAR; CNS; EPSP; NMDAR; PAM; allosteric; brain concentration; potentiator; selectivity
Year: 2016 PMID： 28105280 PMCID： PMC5238474 DOI： 10.1021/acsmedchemlett.6b00388
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345