Hikichi Hirohiko, Tokumaru Yuichi, Taruta Atsuki, Konno Yoshihiro, Karasawa Jun-Ichi, Fukumoto Kenichi, Marumo Toshiyuki, Fujii Yasuyuki, Takahashi Teisuke, Yoshimizu Takao, Chaki Shigeyuki, Hino Noriko, Kojima Naoki
Research Headquarters, Taisho Pharmaceutical Co, Ltd, Saitama, Japan.
Research Headquarters, Taisho Pharmaceutical Co, Ltd, Saitama, Japan.
J Pharmacol Exp Ther. 2025 Jul;392(7):103624. doi: 10.1016/j.jpet.2025.103624. Epub 2025 Jun 6.
Dual orexin receptor antagonists are known to inhibit the orexinergic signaling pathway, leading to promotion of sleep. Here, we report the pharmacological profiles of [(2S)-2-{[3-(5-Fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (vornorexant), also known as ORN0829. In in vitro assays, vornorexant exhibited a high affinity for OX and OX receptors, without any meaningful affinity for other receptors, transporters or ion channels, exerting receptor antagonist activity. Vornorexant had pharmacokinetic profiles with a relatively rapid absorption and short half-life, rapidly occupied the OX and OX receptors in the brain of rats after oral administration and rapidly dissociated from these receptors depending on the plasma concentration. In rats, daily oral administration of vornorexant just before the dark phase reduced the sleep onset latency and prolonged sleep time, and no tolerance developed up to 14 days. Vornorexant also reduced the sleep onset latency and prolonged sleep time in rats that had developed tolerance after daily treatment with the GABA receptor modulator, zolpidem. In addition, vornorexant also enhanced the sleep-promoting effects of zolpidem in rats. Moreover, vornorexant did not impair motor coordination in monotherapy and combination with ethanol in rats. These results indicate that vornorexant has desirable profiles with a rapid sleep onset latency and a short half-life, thereby a lowered risk of next-morning residual activity. Vornorexant could be a promising alternative therapeutic option to GABA receptor modulators for the treatment of insomnia. SIGNIFICANCE STATEMENT: Vornorexant is a novel and potent dual orexin receptor antagonist that was demonstrated to exert sleep-promoting effects by occupying the OX and OX receptors in the brain of rats. Moreover, vornorexant promoted sleep even after switching treatment from zolpidem or when administered in combination with zolpidem in rats. These results suggest that vornorexant possesses properties that are desirable for insomnia drugs.
已知双重食欲素受体拮抗剂可抑制食欲素能信号通路，从而促进睡眠。在此，我们报告了[(2S)-2-{[3-(5-氟吡啶-2-基)-1H-吡唑-1-基]甲基}-1,3-恶唑烷-3-基][5-甲基-2-(2H-1,2,3-三唑-2-基)苯基]甲酮（沃替西汀）的药理学特性，它也被称为ORN0829。在体外试验中，沃替西汀对OX1和OX2受体表现出高亲和力，对其他受体、转运体或离子通道没有任何显著亲和力，发挥受体拮抗剂活性。沃替西汀具有相对快速吸收和短半衰期的药代动力学特征，口服给药后能迅速占据大鼠脑中的OX1和OX2受体，并根据血浆浓度迅速从这些受体上解离。在大鼠中，在黑暗期前每日口服沃替西汀可缩短睡眠起始潜伏期并延长睡眠时间，且在长达14天内未产生耐受性。沃替西汀还可缩短经γ-氨基丁酸（GABA）受体调节剂唑吡坦每日治疗后已产生耐受性的大鼠的睡眠起始潜伏期并延长睡眠时间。此外，沃替西汀还增强了唑吡坦对大鼠的促睡眠作用。而且，沃替西汀在大鼠单一疗法及与乙醇联合使用时均不损害运动协调性。这些结果表明，沃替西汀具有理想的特征，睡眠起始潜伏期短且半衰期短，因此次日早晨残留活性风险较低。沃替西汀可能是治疗失眠的γ-氨基丁酸受体调节剂的一种有前景的替代治疗选择。意义声明：沃替西汀是一种新型强效双重食欲素受体拮抗剂，已证明其通过占据大鼠脑中的OX1和OX2受体发挥促睡眠作用。此外，在大鼠中，即使从唑吡坦转换治疗后或与唑吡坦联合给药时，沃替西汀也能促进睡眠。这些结果表明，沃替西汀具有失眠药物所需的特性。
