腺苷A1受体新配体YZG-404的镇静催眠作用

目的研究新化合物YZG-404与腺苷A1受体（A1R）和腺苷A2A受体（A2AR）的亲和力及其镇静催眠作用。方法采用放射性配体受体竞争结合实验分别测定YZG-404与腺苷A1R和腺苷A2AR的亲和力;采用开阔场实验测定其对小鼠自发活动的影响;采用协同戊巴比妥钠睡眠实验评价其镇静催眠作用。结果 YZG-404对腺苷A1R亲和力较高,Ki值为98.8 nmol/L,而对腺苷A2AR的亲和力较低,Ki值约为9828.8 nmol/L。与溶剂对照组比较,YZG-404（1.25、2.5和5 mg/kg,ig）明显抑制小鼠的自发活动,抑制率分别为26.0%、59.7%和67.1%。另外,YZG-404（1.25、2.5和5 mg/kg,ig）可以明显延长戊巴比妥钠诱导小鼠睡眠时间,延长率分别为49.7%、129.5%和126.0%,并缩短入睡潜伏期,最高缩短率为19.8%。YZG-404能提高阈下剂量戊巴比妥钠诱导小鼠入睡率,最高入睡率达80%,效果与阳性对照药地西泮相当。结论新化合物YZG-404与腺苷A1R亲和力强,并具有强效的镇静催眠作用。

Sedative and hypnotic effects of a novel ligand YZG-404 for adenosine A1 receptor

Objective To examine the affinities of YZG-404,a novel compound,to adenosine A1 receptor（A1R） and adenosine A2A receptor（A2AR） and its sedative and hypnotic effects.Methods Radioligand binding tests were carried out for the affinity property of YZG-404 to adenosine A1R and adenosine A2AR.The influence of YZG-404 on mice spontaneous locomotor activity was investigated by open field test,and sedative and hypnotic effect of YZG-404 on sodium pentobarbital-treated mice was also evaluated.Results YZG-404 had a higher affinity to adenosine A1R than to adenosine A2AR.The values of Ki to adenosine A1R and A2AR were 98.8 and 9828.8 nmol/L,respectively.The spontaneous locomotor activity was significantly decreased by YZG-404 at test doses（1.25,2.5 and 5 mg/kg,ig）,and the decreasing rate was 26.0%,59.7% and 67.1%,respectively.The duration of sleeping in sodium pentobarbital-treated mice was dose-dependently prolonged by YZG-404,which was 49.7%,129.5% and 126.0% as compared to vehicle group.The sleeping latency was significantly decreased by YZG-404,which was 19.8% at 2.5 mg/kg.Furthermore sleep onset in sub-hypnotic dose of sodium pentobarbital treated mice was significantly increased to 80% at the higher dose,which was similar to diazepam.Conclusion YZG-404 may act as a novel ligand for adenosine A1R,and has potent sedative and hypnotic effects.