Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Eur J Pharmacol. 2017 Sep 5;810:26-35. doi: 10.1016/j.ejphar.2017.05.045. Epub 2017 May 25.
KCNH3 (BEC1) is a member of the ether-à-go-go (KCNH) family of voltage-gated K channels. The aim of this study was to determine the pharmacological profiles in vitro and in vivo of a KCNH3 inhibitor N-(4-fluorophenyl)-N'-phenyl-N''-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine (ASP2905). We analyzed the effects of ASP2905 on channel activity in vitro and its neuropharmacological properties in young and aged rats as well as in mice. ASP2905 potently inhibited potassium currents in CHO cells expressing KCNH3 (IC = 9.0nM). In contrast, ASP2905 (≤ 10μM) minimally bound with low affinities to 55 transmembrane proteins. ASP2905 (0.1µM, 1µM) decreased the frequency of spontaneous inhibitory postsynaptic currents in cultured rat hippocampal neurons. In mice, ASP2905 reversed the disruption of spontaneous alternation behavior induced by MK-801 and scopolamine (minimum effective dose of ASP2905: 0.0625mg/kg, po). ASP2905 ameliorated the cognitive deficits of aged rats in step-through passive avoidance (0.0313 and 0.0625mg/kg, po) and Morris water-maze tasks (0.01mg/kg, po) and effectively penetrated the brain. The mean plasma and brain concentrations of ASP2905 reached their maxima (C = 0.399ng/ml and 1.77ng/g, respectively) 1h after a single oral administration and then decreased (t = 1.5-1.6h) (brain plasma ratio = 2.7-4.9). The present study suggests that ASP2905 is a selective, orally administered inhibitor of KCNH3, which can enhance cognitive performance.
KCNH3（BEC1）是电压门控 K 通道醚-ago-go（KCNH）家族的成员。本研究旨在确定 KCNH3 抑制剂 N-（4-氟苯基）-N'-苯基-N''-（嘧啶-2-基甲基）-1,3,5-三嗪-2,4,6-三胺（ASP2905）的体外和体内药理学特征。我们分析了 ASP2905 对表达 KCNH3 的 CHO 细胞中通道活性的影响及其在年轻和老年大鼠以及小鼠中的神经药理学特性。ASP2905 强烈抑制表达 KCNH3 的 CHO 细胞中的钾电流（IC = 9.0nM）。相比之下，ASP2905（≤10μM）以低亲和力最小程度结合 55 种跨膜蛋白。ASP2905（0.1μM，1μM）降低了培养的大鼠海马神经元中自发性抑制性突触后电流的频率。在小鼠中，ASP2905 逆转了 MK-801 和东莨菪碱诱导的自发交替行为的破坏（ASP2905 的最小有效剂量：0.0625mg/kg，po）。ASP2905 改善了老年大鼠在穿梭被动回避（0.0313 和 0.0625mg/kg，po）和 Morris 水迷宫任务（0.01mg/kg，po）中的认知缺陷，并且有效地穿透了大脑。ASP2905 单次口服后 1 小时达到其最大血浆和脑浓度（C = 0.399ng/ml 和 1.77ng/g），然后下降（t = 1.5-1.6h）（脑血浆比 = 2.7-4.9）。本研究表明，ASP2905 是一种选择性的、可口服的 KCNH3 抑制剂，可增强认知表现。
