ASP2905 is a novel, orally active potassium channel KCNH3 inhibitor. ASP2905 can cross the blood-brain barrier to exert antipsychotic effects, while also improving neuropsychiatric symptoms by enhancing cognitive function. ASP2905 is applicable for research in attention-deficit/hyperactivity disorder and schizophrenia[1-2].
In vitro, ASP2905 (0.1–10μM) was applied to HEK293 cells for approximately 2 days. ASP2905 bound to aptazyme- and exon skipping-based riboswitches, significantly upregulating the expression of the reporter gene EGFP, with no significant effect on the viability of HEK293 cells[3]. ASP2905 (0.1–1μM) was administered to primary cultured rat hippocampal neurons for 4 minutes. ASP2905 significantly decreased both the frequency and mean amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs)[4].
In vivo, ASP2905 (0.0313–0.3 mg/kg; orally) was administered to normal ddY mice and juvenile stroke-prone spontaneously hypertensive rats (SHRSP). ASP2905 significantly shortened the finding latency in mice, prolonged the cumulative latency in rats, and concurrently increased the extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex of rats, as well as the alpha band power in electroencephalograms[5]. ASP2905 (0.03–0.3mg/kg; oral administration) was used to treat a mouse model of schizophrenia. ASP2905 significantly reversed the prolonged immobility time in the forced swim test, shortened the finding latency in neonatal mice, and markedly ameliorated the hyperlocomotor activity in mice[6].
References:
[1] Nomura Y, Kim N, Zhu B, et al. Optimization of Exon-Skipping Riboswitches and Their Applications to Control Mammalian Cell Fate. ACS Synth Biol. 2024 Oct 18;13(10):3246-3255.
[2] Ishii Y, Fukunaga K, Cooney A, et al. Switchable and orthogonal gene expression control inside artificial cells by synthetic riboswitches. Chem Commun (Camb). 2024 Jun 4;60(46):5972-5975.
[3] Fukunaga K, Dhamodharan V, Miyahira N, et al. Small-Molecule Aptamer for Regulating RNA Functions in Mammalian Cells and Animals. J Am Chem Soc. 2023 Apr 12;145(14):7820-7828.
[4] Takahashi S, Inamura K, Yarimizu J, et al. Neurochemical and neuropharmacological characterization of ASP2905, a novel potent selective inhibitor of the potassium channel KCNH3. Eur J Pharmacol. 2017 Sep 5;810:26-35.
[5] Takahashi S, Ohmiya M, Honda S, et al. The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder. PLoS One. 2018 Nov 21;13(11):e0207750.
[6] Takahashi S, Okamura A, Yamazaki M, et al. ASP2905, a specific inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3 gene, is psychoactive in mice. Behav Brain Res. 2020 Jan 27;378:112315.
ASP2905是一种新型的、具有口服活性的钾通道KCNH3抑制剂。ASP2905可穿越血脑屏障来发挥抗精神病作用，同时通过增强认知功能以改善神经精神症状。ASP2905可用于注意力缺陷/多动障碍和精神分裂症的相关研究[1-2]。
在体外，ASP2905（0.1–10μM）处理HEK293细胞约2天，ASP2905能够结合基于aptazyme和外显子跳跃的核糖开关，显著上调报告基因EGFP的表达，对HEK293细胞的活性无显著影响[3]。ASP2905（0.1–1μM）处理原代培养的大鼠海马神经元4分钟。ASP2905能够显著降低自发抑制性突触后电流（sIPSCs）的频率和平均振幅[4]。
在体内，ASP2905（0.0313–0.3mg/kg；口服）处理正常ddY小鼠及幼年易卒中自发性高血压大鼠（SHRSP）。ASP2905能够显著缩短小鼠的寻找潜伏期，并延长大鼠的累积潜伏期，同时增加大鼠内侧前额叶皮层中多巴胺和乙酰胆碱的细胞外水平以及脑电图的α波段功率[5]。ASP2905（0.03–0.3mg/kg；口服给药）处理精神分离小鼠模型。ASP2905能够显著逆转小鼠在强迫游泳测试中不动时间的延长，并显著缩短新生期小鼠的寻找潜伏期，同时显著改善小鼠的自发活动亢进[6]。