Katzman Brooke M, Perszyk Riley E, Yuan Hongjie, Tahirovic Yesim Altas, Sotimehin Ayodeji E, Traynelis Stephen F, Liotta Dennis C
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States.
Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, United States.
Bioorg Med Chem Lett. 2015 Dec 1;25(23):5583-8. doi: 10.1016/j.bmcl.2015.10.046. Epub 2015 Oct 19.
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.
NMDA受体介导兴奋性突触传递中缓慢的钙离子通透成分，并参与包括学习和记忆在内的多种正常脑功能。NMDA受体过度激活可导致与中风、创伤性脑损伤和癫痫相关的缺血中的细胞死亡和异常兴奋。我们探索了一系列以亚氨基噻唑烷酮环为特征的新型NMDA受体功能非竞争性变构调节剂。这些化合物的饱和浓度在不同程度上抑制NMDA受体，这增加了它们在病理情况下可能减弱过度激活同时保留一些最小受体功能的可能性，这可能会限制副作用。同类最佳的化合物具有亚微摩尔的IC50值，并且对含GluN2C和GluN2D的受体表现出适度的偏好。
