Department of Pharmacogenetics, Federal State Budgetary Institution "Research Zakusov Institute of Pharmacology", Baltiyskaya Street 8, 125315 Moscow, Russia.
Int J Mol Sci. 2023 May 31;24(11):9580. doi: 10.3390/ijms24119580.
Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABA receptor's benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect. To prove our main hypothesis of Sigma1R involvement in GABA receptor-dependent pharmacological effects, we performed a series of experiments on BALB/c and ICR mice using Sigma1R ligands to study anxiolytic effects of benzodiazepine tranquilizers diazepam (1 mg/kg i.p.) and phenazepam (0.1 mg/kg i.p.) in the elevated plus maze test, the anticonvulsant effects of diazepam (1 mg/kg i.p.) in the pentylenetetrazole-induced seizure model, and the hypnotic effects of pentobarbital (50 mg/kg i.p.). Sigma1R antagonists BD-1047 (1, 10, and 20 mg/kg i.p.), NE-100 (1 and 3 mg/kg i.p.), and Sigma1R agonist PRE-084 (1, 5, and 20 mg/kg i.p.) were used in the experiments. Sigma1R antagonists have been found to attenuate while Sigma1R agonists can enhance GABARs-dependent pharmacological effects.
先前的非苯二氮䓬类抗焦虑药法莫替佐的药物开发研究已经确定了两组事实。首先，法莫替佐可预防应激引起的 GABA 受体苯二氮䓬结合部位结合能力下降。其次，法莫替佐是 Sigma1R 伴侣激动剂，暴露于 Sigma1R 拮抗剂会阻断其抗焦虑作用。为了证明我们关于 Sigma1R 参与 GABA 受体依赖性药物作用的主要假设，我们使用 Sigma1R 配体在 BALB/c 和 ICR 小鼠上进行了一系列实验，以研究苯二氮䓬类镇静剂地西泮（1mg/kg，ip）和苯甲二氮䓬（0.1mg/kg，ip）在高架十字迷宫测试中的抗焦虑作用、地西泮（1mg/kg，ip）在戊四唑诱导的惊厥模型中的抗惊厥作用以及戊巴比妥（50mg/kg，ip）的催眠作用。Sigma1R 拮抗剂 BD-1047（1、10 和 20mg/kg，ip）、NE-100（1 和 3mg/kg，ip）和 Sigma1R 激动剂 PRE-084（1、5 和 20mg/kg，ip）在实验中被使用。研究发现，Sigma1R 拮抗剂可减弱，而 Sigma1R 激动剂可增强 GABA 受体依赖性药物作用。
