A novel class of negative allosteric modulators of NMDA receptor function. Issue 23 (1st December 2015)

• Record Type: Journal Article
• Authors: Katzman, Brooke M.; Perszyk, Riley E.; Yuan, Hongjie; Tahirovic, Yesim Altas; Sotimehin, Ayodeji E.; Traynelis, Stephen F.; Liotta, Dennis C.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 23(2015)
• Page Start: 5583
• Page End: 5588
• Publication Date: 2015-12-01
• Subjects: GluN2 -- Glutamate -- Noncompetitive antagonist -- N-Methyl-d-aspartate -- Neuroprotection; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.046
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: NMDA receptors mediate a slow Ca 2+ -permeable component of excitatory synaptic transmission, and are involved in numerous normal brain functions including learning and memory. NMDA receptor over-activation can lead to cell death and abnormal excitation in ischemia associated with stroke, traumatic brain injury, and epilepsy. We have explored a series of novel noncompetitive allosteric modulators of NMDA receptor function characterized by an iminothiazolidinone ring. Saturating concentrations of these compounds inhibit NMDA receptors to varying maximal extents, raising the possibility that they may attenuate over-activation in pathological situations while preserving some minimal receptor function, which may limit side-effects. The best in class compounds have sub-micromolar IC50 values and show modest preference for GluN2C- and GluN2D-containing receptors.