Mallamo J P, Earley W G, Kumar V, Subramanyam C, Dority J A, Miller M S, DeHaven-Hudkins D L, Ault B, Herrmann J L, Dung J S
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426-0900.
J Med Chem. 1994 Dec 23;37(26):4438-48. doi: 10.1021/jm00052a003.
A series of novel N-methyl-D-aspartate antagonists acting at the phencyclidine site has been identified. Compound 2 has a Ki = 8 +/- 1 nM (vs [3H]thienylcyclidine, [3H]TCP) as a mixture of enantiomers. Resolution and further testing indicate that (-)-2, Ki = 4 +/- 0.7 nM, is a potent and selective TCP site ligand with neuroprotective activity in cultured neurons in the presence of excitotoxic concentrations of NMDA (IC50 = 26 nM). Compound (-)-2 is > 1000-fold selective for the TCP site vs a panel of receptor types including opiate, adrenergic, serotonergic, dopamine, adenosine, dihydropyridine, and benzodiazepine and displays increased selectivity for the activated (open) NMDA receptor-ion channel complex vs PCP and MK801 as measured by patch recordings in cultured, voltage-clamped neurons. Highly enhanced "open-channel" selectivity leads to tentative classification of these ligands as uncompetitive vs NMDA. Ligands with these characteristics may enable deconvolution of the pharmacologic effects associated with typical noncompetitive NMDA antagonists. We report here on the identification, synthesis, and activity of compounds of this structural class.
已鉴定出一系列作用于苯环己哌啶位点的新型N-甲基-D-天冬氨酸拮抗剂。化合物2作为对映体混合物，其Ki = 8 +/- 1 nM（相对于[3H]噻吩环己哌啶，[3H]TCP）。拆分和进一步测试表明，(-)-2，Ki = 4 +/- 0.7 nM，是一种强效且选择性的TCP位点配体，在存在兴奋性毒性浓度NMDA（IC50 = 26 nM）的情况下，对培养的神经元具有神经保护活性。相对于包括阿片、肾上腺素能、血清素能、多巴胺、腺苷、二氢吡啶和苯二氮卓在内的一系列受体类型，化合物(-)-2对TCP位点的选择性大于1000倍，并且通过在培养的电压钳制神经元中进行膜片钳记录测量，相对于PCP和MK801，其对活化（开放）的NMDA受体-离子通道复合物的选择性增加。高度增强的“开放通道”选择性导致这些配体相对于NMDA被初步分类为非竞争性。具有这些特征的配体可能有助于对与典型非竞争性NMDA拮抗剂相关的药理作用进行反卷积分析。我们在此报告此类结构化合物的鉴定、合成和活性。
