A novel class of negative allosteric modulators of NMDA receptor function

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Katzman, Brooke M.¹  Perszyk, Riley E.²  Yuan, Hongjie²  Tahirovic, Yesim Altas¹  Sotimehin, Ayodeji E.²  Traynelis, Stephen F.²  Liotta, Dennis C.¹ 

[1] Emory Univ, Dept Chem, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA

关键词: GluN2;    Glutamate;    Noncompetitive antagonist;    N-Methyl-D-aspartate;    Neuroprotection;   

DOI  :  10.1016/j.bmcl.2015.10.046

来源: Elsevier

【 摘 要 】

NMDA receptors mediate a slow Ca2+-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. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

Free