Tang A H, Franklin S R, Carter D B, Sethy V H, Needham L M, Jacobsen E J, Von Voigtlander P F
Pharmacia & Upjohn Inc., Kalamazoo, MI 49001, USA.
Psychopharmacology (Berl). 1997 Jun;131(3):255-63. doi: 10.1007/s002130050291.
PNU-101017 is a chemically novel ligand at the benzodiazepine recognition site of cloned GABAA receptors. It was reported to potentiate GABA-mediated chloride current in cultured cells with a moderate intrinsic activity and a biphasic dose-response relationship. In this study, we confirmed that PNU-101017 has a partial agonist-like effect in the antagonism of metrazole-induced seizures in mice. It produced no sedation or ataxia, but did antagonize diazepam-induced motor deficit of mice in the rotarod test. PNU-101017 was weakly active in anti-conflict anxiolytic tests, but attenuated the plasma corticosteroid response to mild stress in rats. It also antagonized stress-induced elevation of cerebellar cGMP levels in mice. Like chlordiazepoxide, it increased drinking of saline solution in thirsty rats. PNU-101017 did not potentiate the CNS-depressant effects of ethanol, and produced no evidence of physical dependence when administered repeatedly. Agonists with low intrinsic activity at the benzodiazepine receptor, such as PNU-101017, should be further explored for therapeutic uses.
PNU - 101017是一种在克隆的GABAA受体苯二氮䓬识别位点具有化学新颖性的配体。据报道，它能增强培养细胞中GABA介导的氯离子电流，具有中等内在活性和双相剂量反应关系。在本研究中，我们证实PNU - 101017在拮抗戊四氮诱导的小鼠癫痫发作中具有部分激动剂样作用。它不会产生镇静或共济失调，但在转棒试验中确实能拮抗地西泮诱导的小鼠运动功能缺陷。PNU - 101017在抗冲突抗焦虑试验中活性较弱，但能减弱大鼠对轻度应激的血浆皮质类固醇反应。它还能拮抗应激诱导的小鼠小脑cGMP水平升高。与氯氮卓一样，它能增加口渴大鼠的盐水饮用量。PNU - 101017不会增强乙醇的中枢神经系统抑制作用，反复给药时也没有产生身体依赖性的证据。像PNU - 101017这样在苯二氮䓬受体具有低内在活性的激动剂，应进一步探索其治疗用途。
