A novel class of negative allosteric modulators of NMDA receptor function

作者：Katzman Brooke M; Perszyk Riley E; Yuan Hongjie; Tahirovic Yesim Altas; Sotimehin Ayodeji E; Traynelis Stephen F; Liotta Dennis C^*

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(23): 5583-5588.

DOI：10.1016/j.bmcl.2015.10.046

• GluN2
• Glutamate
• Noncompetitive antagonist
• N-Methyl-D-aspartate
• Neuroprotection

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.

• 出版日期2015-12-1