化合物H057镇静催眠作用评价  

Evaluation of the sedative and hypnotic effects of H057

作　　者：王晓冲[1] 董静文 赵香玉[1] 王耀[1] 胡伟[1] 张建军[1] 

机构地区：[1]中国医学科学院北京协和医学院药物研究所新药作用机制研究和药效评价北京市重点实验室,北京100050

出　　处：《中国药理学通报》2016年第5期638-642,共5页Chinese Pharmacological Bulletin

基　　金：国家科技部"重大新药创制"科技重大专项(No2012ZX09301002001002)

摘　　要：目的评价化合物H057镇静催眠的药效学,并对其相关机制进行初步研究。方法利用开场实验测定H057对小鼠自主活动的影响,评价其中枢镇静作用;通过协同阈下剂量戊巴比妥钠诱导小鼠睡眠和H057直接诱导小鼠睡眠实验,评价其催眠作用;利用微透析技术测定H057对大鼠大脑皮层细胞外液抑制性氨基酸GABA和单胺神经递质5-HT、NE含量的影响。结果与溶剂对照组相比,H057(5、25 mg·kg^(-1),i.p.)组能明显抑制小鼠自主活动,抑制率分别为25%和66%;H057能明显增加阈下剂量戊巴比妥钠(25 mg·kg^(-1),ip)诱导小鼠的入睡率,3、5 mg·kg^(-1)组小鼠入睡率分别增加为62.5%和87.5%;H057(≥60 mg·kg^(-1),i.p.)可直接诱导小鼠100%入睡,60 mg·kg^(-1)剂量下诱导小鼠睡眠潜伏期和睡眠时间分别为(24±11)min和(97±15)min;微透析实验表明,H057(25 mg·kg^(-1),i.p.)能明显升高大鼠大脑皮层细胞外液GABA含量,给药10 min后升高了26%;能明显降低5-HT和NE的含量,给药1 h后分别降低了50%和38%。结论化合物H057具有很强的镇静催眠作用,升高大脑皮层细胞外液GABA含量,同时降低单胺神经递质5-HT和NE的含量可能是其发挥镇静催眠作用的机制之一。Aim To investigate the sedative and hyp-notic effects of a novel compound H057 . Methods The sedative activity of H057 was investigated by re-cording the spontaneous locomotor activity in mice. The hypnotic property was evaluated by the latency and duration of loss of righting reflex( LORR) in mice and effect of H057 on the sleep onset in subthreshold dos-age of sodium pentobarbital treated mice. The extracel-lular levels of GABA and monoamine neurotransmitters in in cerebral cortex were measured by microdialysis in vivo. Results The spontaneous locomotor activity was decreased by 25% and 66% in H057 ( 5 , 25 mg · kg-1 ,i. p. ) treated mice, respectively. H057 ( 3, 5 mg·kg-1 ,i. p. ) increased the sleep onset to 62. 5%and 87. 5% in subthreshold dosage of sodium pentobar-bital(25 mg·kg-1,i. p. ) treated mice. H057(≥60 mg· kg-1 , i. p. ) could completely induce LORR in mice. The latency of LORR at dose of 60 mg · kg-1 was (24 ± 11) min and the duration of LORR was (96 ± 15 ) min. In vivo mircodialysis revealed that H057 (25 mg·kg-1 , i. p. ) could significantly increase the GABA level by 26% and decrease the 5-HT and NE levels by 50% and 38% in cerebral cortex in mice. Conclusion H057 has potent sedative and hypnotic effects, which may be closely related to the increased content of GABA and the decreased contents of 5-HT and NE in the extracellular fluid in cerebral cortex.

关 键 词：镇静催眠 自主活动 翻正反射消失 微透析 Γ氨基丁酸 单胺神经递质 

分 类 号：R-332[医药卫生] R322.81