定型抗精神病薬pimozideの構造展開により開発した新規T型Ca^２＋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

抄録

In this study, we examined the selectivity, electrophysiological properties and analgesic activity of KTtp38, a novel inhibitor of T-type Ca²⁺ (Ca_v3) 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 Ca_v3.2-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 Ca_v3.1-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 Ca_v3.2 activity, in mice. KTtp-38 also reversed oxaliplatin-induced peripheral neuropathy in wild-type, but not Ca_v3.2-null, mice. The T_1/2 (h) of KTtp38 and pimozide in the blood was 2.42 and 2.47, respectively. Collectively, KTtp-38 is considered a state-dependent, selective Ca_v3 inhibitor and useful as an analgesic.