Ault B, Miller M S, Kelly M D, Hildebrand L M, Earley W G, Luttinger D, Mallamo J P, Ward S J
Department of Neuroscience, Sanofi Winthrop Inc., Collegeville, PA 19426-0900, USA.
Neuropharmacology. 1995 Dec;34(12):1597-606. doi: 10.1016/0028-3908(95)00125-5.
NMDA channel blockers are potentially advantageous therapeutic agents for the treatment of ischemia and head trauma, which greatly elevate extracellular glutamate, because they should most effectively inhibit high levels of receptor activation. A novel high affinity TCP site ligand, WIN 63480, does not produce MK-801- or PCP-like behavioral activation at anti-ischemic doses. While WIN 63480, MK-801 and PCP were all observed to be effective blockers of open NMDA channels, WIN 63480 had much less access to closed NMDA channels. This difference may be due to the fact that WIN 63480 is hydrophilic (logD = -4.1) while MK-801 and PCP are lipophilic (logD = +1.8). In vivo, closed channel access may result in a non-competitive profile of antagonism for MK-801 and PCP compared to a more uncompetitive profile for WIN 63480. Release of glutamate, and depolarization, are likely to produce a high level of NMDA receptor activation in ischemic areas compared to normal tissue. Consequently, at anti-ischemic doses, WIN 63480 may produce less inhibition of physiological NMDA-mediated processes in neural systems involved in behavioral regulation than MK-801 or PCP, leading to an improved side effect profile.
NMDA通道阻滞剂是治疗局部缺血和头部创伤的潜在优势治疗药物，局部缺血和头部创伤会大幅提高细胞外谷氨酸水平，因为它们应能最有效地抑制高水平的受体激活。一种新型高亲和力TCP位点配体WIN 63480在抗缺血剂量下不会产生类似MK - 801或PCP的行为激活作用。虽然WIN 63480、MK - 801和PCP都被观察到是开放NMDA通道的有效阻滞剂，但WIN 63480进入关闭的NMDA通道的能力要弱得多。这种差异可能是由于WIN 63480是亲水性的（logD = -4.1），而MK - 801和PCP是脂溶性的（logD = +1.8）。在体内，与WIN 63480更具非竞争性的拮抗作用相比，进入关闭通道可能导致MK - 801和PCP呈现非竞争性拮抗作用。与正常组织相比，谷氨酸的释放和去极化可能会在缺血区域产生高水平的NMDA受体激活。因此，在抗缺血剂量下，与MK - 801或PCP相比，WIN 63480对参与行为调节的神经系统中生理NMDA介导的过程的抑制作用可能更小，从而改善副作用情况。
