中枢腺苷A_1受体参与N^6-取代腺苷衍生物YZG-330对小鼠体温的调节  

Central-adenosine A_1 receptor involved in the thermal regulation effect of YZG-330, a N^6-substituted adenosine derivative, in mice

作　　者：贾少博 张缨 石建功 张建军 

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050 [2]Department of Anatomy and Neurobiology, Dalhousie University, Canada, 15000

出　　处：《药学学报》2015年第6期690-696,共7页Acta Pharmaceutica Sinica

基　　金：国家“重大新药创制”科技重大专项资助项目(2012ZX09301002001002);北京市重点实验室资助项目(BZ0150)

摘　　要：腺苷受体在调节动物体温及觉醒状态的过程中扮演了重要作用。在前期研究中,本实验室使用氨茶碱(血脑屏障可透过性非选择性腺苷受体拮抗剂)拮抗了腺苷衍生物YZG-330[(2R,3S,4R,5R)-2-(hydroxymethyl)-5-(6-(((R)-1-phenylpropyl)amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol]对小鼠体温的降低作用。本文进一步研究了化合物YZG-330对小鼠降温的作用特点,并通过给予有代表性的腺苷受体拮抗剂来确定化合物发挥药效的受体亚型。结果表明,YZG-330降低小鼠体温作用的强度和时间具有剂量依赖性,在口服0.25、1和4 mg·kg-1YZG-330 3 h内,小鼠体温下降的极值分别为(1.2±0.3)℃、(3.6±0.4)℃(P<0.001)及(7.4±0.5)℃(P<0.001);体温低于34℃的时间分别为0、(10±5)及(153±4)min。腹腔注射各种拮抗剂20 min后口服4 mg·kg-1 YZG-330,3 h内腺苷A1受体拮抗剂(8-cyclopentyl-1,3-dipropylxanthine,DPCPX)能有效逆转YZG-330的降温作用,动物体温下降的极值为(3.5±0.7)℃(P<0.001),体温低于34℃的时间为(8±6)min(P<0.001);而腺苷A2a受体的拮抗剂[7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,SCH-58261]对YZG-330的降温作用无明显影响;血脑屏障不可透过性非选择性腺苷受体拮抗剂[8-(p-sulfophenyl)-theophylline hydrate,8-SPT]不能逆转YZG-330对小鼠体温的降低。结果说明中枢腺苷A1受体参与了YZG-330对小鼠的降温作用。Adenosine receptors （AR） play an important role in the regulation processes for body temperature and vigilance states. During our previous studies, we noticed that aminophylline （a non-selective, blood-brain- barrier penetrably AR antagonist） could attenuate the effects of YZG-330 [（2R,3S,4R, 5R）-2-（hydroxymethyl）- 5-（6-（（（R）-l-phenylpropyl）amino）-9H-purin-9-yl）tetrahydrofuran-3, 4-diol] on lowering the body temperature. Hereby, we focused ourselves on the character of thermal regulation effect of YZG-330 in mice and tried to specify the receptor subtype via giving typical adenosine receptor antagonists. The results showed that both of the magnitude and lasting time of the effect that YZG-330 played on decreasing body temperature are in a dose-dependent manner： within the next 3 hour after intragastric administration （ig） of 0.25, 1 or 4 mg .kg-1 YZG-330, the extreme values on body temperature decreasing were （1.2±0.3） ℃, （3.6±0.4） ℃ （P〈0.001） and （7.4±0.5） ℃ （P〈0.001）, separately; whereas the duration that body temperature below 34 ℃ were 0, （10±5） and （153±4） rain, separately. Adenosine A~ receptor （AjR） antagonist （DPCPX） could effectively reverse YZG-330＇s effect on decreasing body temperature, with intraperitoneal administration of DPCPX （5 mg .kg-1） 20 min prior than YZG-330 （4 mg·kg-1, ig）, the extreme value on body temperature decreasing was （3.5 ±0.7） ℃ （P〈0.001）, the duration that body temperature below 34 ℃ was （8±6） min （P〈0.001）. However, adenosine A2a receptor antagonist, SCH-58261, did not show any influence on the effects of YZG-330 at all. Combined with the fact that 8-SPT （a non-selective, blood-brain-barrier impenetrably AR antagonist） did not reverse the effect of YZG-330, we come to the conclusion that central-adenosine A1 receptor plays a significant role on the thermal regulation effect of YZG-330.

关 键 词：体温调节 腺苷受体 腺苷受体拮抗剂 

分 类 号：R963[医药卫生—微生物与生化药学]