Marston H M, Finlayson K, Maemoto T, Olverman H J, Akahane A, Sharkey J, Butcher S P
Fujisawa Institute of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh, UK.
J Pharmacol Exp Ther. 1998 Jun;285(3):1023-30.
The behavioral profile of a range of adenosine receptor ligands was examined in rats using a locomotor activity model. Adenosine receptor agonists, including the selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) and the A2A agonist, 2-[(2-aminoethylamino)carbonylethyl-phenylethylamino]- 5'-ethylcarboxa midoadenosine (APEC), reduced spontaneous motor activity in a dose-dependent manner. CPA-induced locomotor depression was attenuated by adenosine A1 receptor selective antagonists, such as 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-2-piperidine ethanol (FK453), and (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-piperidin-2-yl acetic acid (FK352), but not by the A2A receptor antagonist, (E)-1,3-dipropyl-8-(3, 4-dimethoxystyryl)-7-methylxanthine (KF17837). By contrast, APEC-induced hypolocomotion was attenuated by KF17837 but not by DPCPX, confirming that adenosine A1 and A2A receptor activation mediates locomotor output independently. It was found that two peripheral adenosine receptor antagonists, 8-(p-sulphophenyl)-1, 3-dipropylxanthine (DPSPX) and 8-(p-sulphophenyl)-1, 3-dimethylxanthine (8-PST), did not alter CPA-induced hypolocomotion. This confirmed that pharmacological reversal of the adenosine A1 receptor-mediated response involved a central site of drug action. The relationship between occupancy of central adenosine A1 receptors and behavioral effect was therefore assessed. Regression analysis on log transformed data confirmed associations between antagonist affinity for brain [3H]DPCPX binding sites and, in order of increasing significance, the equivalent behavioral dose (EBD) for reversal of CPA-induced hypolocomotion (r2 = 0.32), the serum concentration of drug (r2 = 0.65), and most significantly with the brain concentration of drug detected 20 min after administration of the (EBD) (r2 = 0.95). These data suggest that competition between agonists and antagonists, for occupancy of central adenosine A1 receptors, is intrinsic to the pharmacological reversal of CPA-induced hypolocomotion. The validity of the model as a simple predictive screen for the blood/brain barrier permeability of adenosine A1 receptor antagonists was thereby confirmed.
使用运动活动模型在大鼠中研究了一系列腺苷受体配体的行为特征。腺苷受体激动剂，包括选择性A1受体激动剂N6-环戊基腺苷（CPA）和A2A激动剂2-[(2-氨基乙氨基)羰基乙基-苯乙氨基]-5'-乙基羧酰胺腺苷（APEC），以剂量依赖性方式降低自发运动活性。CPA诱导的运动抑制被腺苷A1受体选择性拮抗剂如8-环戊基-1,3-二丙基黄嘌呤（DPCPX）、(R)-1-[(E)-3-(2-苯基吡唑并[1,5-a]吡啶-3-基)-丙烯酰基]-2-哌啶乙醇（FK453）和(R)-1-[(E)-3-(2-苯基吡唑并[1,5-a]吡啶-3-基)-丙烯酰基]-哌啶-2-基乙酸（FK352）减弱，但不被A2A受体拮抗剂(E)-1,3-二丙基-8-(3,4-二甲氧基苯乙烯基)-7-甲基黄嘌呤（KF17837）减弱。相比之下，APEC诱导的运动减少被KF17837减弱，但不被DPCPX减弱，证实腺苷A1和A2A受体激活独立介导运动输出。发现两种外周腺苷受体拮抗剂8-(对磺基苯基)-1,3-二丙基黄嘌呤（DPSPX）和8-(对磺基苯基)-1,3-二甲基黄嘌呤（8-PST）不改变CPA诱导的运动减少。这证实了腺苷A1受体介导反应的药理学逆转涉及药物作用的中枢位点。因此评估了中枢腺苷A1受体占有率与行为效应之间的关系。对对数转换数据的回归分析证实了拮抗剂对脑[3H]DPCPX结合位点的亲和力与CPA诱导的运动减少逆转的等效行为剂量（EBD）（r2 = 0.32）、药物血清浓度（r2 = 0.65）以及给药（EBD）后20分钟检测到的药物脑浓度（r2 = 0.95）之间的关联，且显著性依次增加。这些数据表明激动剂和拮抗剂之间对中枢腺苷A1受体占有率的竞争是CPA诱导的运动减少药理学逆转的内在因素。从而证实了该模型作为腺苷A1受体拮抗剂血脑屏障通透性简单预测筛选方法的有效性。
