定型抗精神病薬pimozideの構造展開により開発した新規T型Ca２＋チャネル阻害薬KTtp38：チャネル選択性、電気生理学的特徴、鎮痛活性の評価

• Published in: 日本薬理学会年会要旨集 p. 1-B-SS06-6
• Main Authors: 豊岡, 尚樹, 笠波, 嘉人, 岡田, 卓哉, 高島, 康宏, 坪田, 真帆, 石川, 千浩, 川瀬, 篤史, 川畑, 篤史, 長南, 百香, 吉田, 繁, 木野, 貴博, 関口, 富美子, 大久保, つや子
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: analgesic; Ca2+ channel; pain; patch clamp
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.96.0_1-B-SS06-6

In this study, we examined the selectivity, electrophysiological properties and analgesic activity of KTtp38, a novel inhibitor of T-type Ca2+ (Cav3) channels, developed by structural modification of pimozide, a typical antipsychotic agent. The IC50 value (μM) of KTtp38 was 0.0934 and 1.109 for inhibiting Cav3.2-dependent currents in response to a test pulse of -20 mV from holding potentials (HPs) of -80 and -110 mV, respectively, indicating a state dependency. The IC50 of KTtp38 for inhibiting Cav3.1-depedent currents caused by the test pulse from HP of -80 mV was 0.217 μM. Pimozide, but not KTtp38, at 1 μM completely inhibited the specific bindings of [3H]-spiperone to D2 and D3 receptors in rat striatal membrane fractions. In isolated rat jugular vein rings, the 5-HT2 receptor-mediated contraction was inhibited by pimozide, but not KTtp38, at 10 μM. In mice, i.p. administration of pimozide, but not KTtp38, caused catalepsy. KTtp38 abolished somatic and visceral pain caused by an H2S donor, known to enhance Cav3.2 activity, in mice. KTtp-38 also reversed oxaliplatin-induced peripheral neuropathy in wild-type, but not Cav3.2-null, mice. The T1/2 (h) of KTtp38 and pimozide in the blood was 2.42 and 2.47, respectively. Collectively, KTtp-38 is considered a state-dependent, selective Cav3 inhibitor and useful as an analgesic.