Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, North Carolina (G.W.K).
Department of Pharmacology and Chemical Biology (S.J.M, P.L., R.J.D., S.F.T.), Department of Chemistry (L.J.W., Y.A.T., D.S.M., Z.W.D., D.C.L.), Emory University, Atlanta, Georgia; NeurOp Inc., Atlanta, Georgia (S.J.M., K.P.R., L.J.W., Y.A.T, P.L., D.S.M., Z.W.D., G.W.K., R.Z.), and TRPblue Inc., Durham, North Carolina (G.W.K)
J Pharmacol Exp Ther. 2021 Oct;379(1):41-52. doi: 10.1124/jpet.120.000370. Epub 2021 Sep 7.
We describe a clinical candidate molecule from a new series of glutamate -methyl-d-aspartate receptor subunit 2B-selective inhibitors that shows enhanced inhibition at extracellular acidic pH values relative to physiologic pH. This property should render these compounds more effective inhibitors of -methyl-d-aspartate receptors at synapses responding to a high frequency of action potentials, since glutamate-containing vesicles are acidic within their lumen. In addition, acidification of penumbral regions around ischemic tissue should also enhance selective drug action for improved neuroprotection. The aryl piperazine we describe here shows strong neuroprotective actions with minimal side effects in preclinical studies. The clinical candidate molecule NP10679 has high oral bioavailability with good brain penetration and is suitable for both intravenous and oral dosing for therapeutic use in humans. SIGNIFICANCE STATEMENT: This study identifies a new series of glutamate -methyl-d-aspartate (NMDA) receptor subunit 2B-selective negative allosteric modulators with properties appropriate for clinical advancement. The compounds are more potent at acidic pH, associated with ischemic tissue, and this property should increase the therapeutic safety of this class by improving efficacy in affected tissue while sparing NMDA receptor block in healthy brain.
我们描述了一种新型谷氨酸 -N- 甲基 -D- 天冬氨酸（NMDA）受体 2B 亚单位选择性抑制剂的临床候选药物分子，与生理 pH 值相比，该分子在细胞外酸性 pH 值下的抑制作用增强。由于含有谷氨酸的囊泡在其腔室内呈酸性，因此该特性应使这些化合物成为对高频动作电位起反应的突触处 NMDA 受体更有效的抑制剂。此外，缺血组织周围半影区的酸化也应增强选择性药物作用，从而改善神经保护作用。我们在这里描述的芳基哌嗪在临床前研究中具有很强的神经保护作用，且副作用最小。临床候选药物 NP10679 具有很高的口服生物利用度，良好的脑穿透性，适用于静脉内和口服给药，可用于人类的治疗。重要性声明：本研究确定了一系列新型的谷氨酸 -N- 甲基 -D- 天冬氨酸（NMDA）受体 2B 亚单位选择性负变构调节剂，具有适合临床进展的特性。这些化合物在酸性 pH 值下（与缺血组织相关）的活性更强，这一特性通过提高受影响组织的疗效，同时避免健康大脑中的 NMDA 受体阻断，从而提高该类药物的治疗安全性。
