首页> 外文OA文献 >Species differences in brain adenosine A1 receptor pharmacology revealed by use of xanthine and pyrazolopyridine based antagonists
【2h】

Species differences in brain adenosine A1 receptor pharmacology revealed by use of xanthine and pyrazolopyridine based antagonists

机译:通过使用基于黄嘌呤和吡唑并吡啶的拮抗剂揭示脑腺苷A1受体药理学上的物种差异

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务,本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文,但由于OA文献来源多样且变更频繁,仍可能出现获取不到、文献不完整或与标题不符等情况,如果获取不到我们将提供退款服务。请知悉。

摘要

The pharmacological profile of adenosine A1 receptors in human, guinea-pig, rat and mouse brain membranes was characterized in a radioligand binding assay by use of the receptor selective antagonist, [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]-DPCPX).The affinity of [3H]-DPCPX binding sites in rat cortical and hippocampal membranes was similar. Binding site affinity was higher in rat cortical membranes than in membranes prepared from guinea-pig cortex and hippocampus, mouse cortex and human cortex. pKD values (M) were 9.55, 9.44, 8.85, 8.94, 8.67, 9.39 and 8.67, respectively. The binding site density (Bmax) was lower in rat cortical membranes than in guinea-pig or human cortical membranes.The rank order of potency of seven adenosine receptor agonists was identical in each species. With the exception of 5′-N-ethylcarboxamidoadenosine (NECA), agonist affinity was 3.5–26.2 fold higher in rat cortical membranes than in human and guinea-pig brain membranes; affinity in rat and mouse brain membranes was similar. While NECA exhibited 9.3 fold higher affinity in rat compared to human cortical membranes, affinity in other species was comparable. The stable GTP analogue, Gpp(NH)p (100 μM) reduced 2-chloro-N6-cyclopentyladenosine (CCPA) affinity 7–13.9 fold, whereas the affinity of DPCPX was unaffected.The affinity of six xanthine-based adenosine receptor antagonists was 2.2–15.9 fold higher in rat cortical membranes compared with human or guinea-pig membranes. The rank order of potency was species-independent. In contrast, three pyrazolopyridine derivatives, (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinebutyric acid (FK838) exhibited similar affinity in human, guinea-pig, rat and mouse brain membranes. pKi values (M) for [3H]-DPCPX binding sites in human cortical membranes were 9.31, 7.52 and 7.92, respectively.Drug affinity for adenosine A2A receptors was determined in a [3H]-2-[4-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine ([3H]-CGS 21680) binding assay in rat striatal membranes. The pyrazolopyridine derivatives, FK453, FK838 and FK352 exhibited pKi values (M) of 5.90, 5.92 and 4.31, respectively, compared with pKi values of 9.31, 8.18 and 7.57 determined in the [3H]-DPCPX binding assay in rat cortical membranes. These novel pyrazolopyridine derivatives therefore represent high affinity, adenosine A1 receptor selective drugs that, in contrast to xanthine based antagonists, exhibit similar affinity for [3H]-DPCPX binding sites in human, rat, mouse and guinea-pig brain membranes.
机译:通过使用受体选择性拮抗剂[3H] -8-环戊基-1,3-二丙基黄嘌呤([3H]进行放射性配体结合测定,对人,豚鼠,大鼠和小鼠脑膜中腺苷A1受体的药理特性进行了表征。 ] -DPCPX)。大鼠皮质和海马膜中[3H] -DPCPX结合位点的亲和力相似。在大鼠皮质膜中的结合位点亲和力高于从豚鼠皮质和海马,小鼠皮质和人皮质制备的膜。 pKD值(M)分别为9.55、9.44、8.85、8.94、8.67、9.39和8.67。大鼠皮膜的结合位点密度(Bmax)低于豚鼠或人皮膜的结合位点.7种腺苷受体激动剂的效价等级顺序在每个物种中相同。除5'-N-乙基羧酰胺基腺苷(NECA)外,大鼠皮膜的激动剂亲和力比人和豚鼠的脑膜高3.5-26.2倍。大鼠和小鼠脑膜的亲和力相似。尽管NECA在大鼠中的亲和力比人类皮质膜高9.3倍,但在其他物种上的亲和力却相当。稳定的GTP类似物Gpp(NH)p(100μm)将2-氯-N6-环戊基腺苷(CCPA)的亲和力降低了7-13.9倍,而DPCPX的亲和力未受影响。六个基于黄嘌呤的腺苷受体拮抗剂的亲和力为与人或豚鼠的膜相比,大鼠的皮膜高2.2-15.9倍。效力的等级顺序与物种无关。相反,三种吡唑并吡啶衍生物,(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),(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)和6-氧代-3-(2 -苯基吡唑并[1,5-a]吡啶-3-基)-1(6H)-哒嗪丁酸(FK838)在人,豚鼠,大鼠和小鼠的脑膜中表现出相似的亲和力。人皮膜中[3H] -DPCPX结合位点的pKi值(M)分别为9.31、7.52和7.92。在[3H] -2- [4-(2-羧乙基)]中测定对腺苷A2A受体的药物亲和力大鼠纹状体膜中的苯乙氨基] -5'-N-乙基羧酰胺基腺苷([3H] -CGS 21680)结合测定。吡唑并吡啶衍生物FK453,FK838和FK352的pKi值(M)分别为5.90、5.92和4.31,而在大鼠皮膜[3H] -DPCPX结合试验中测定的pKi值为9.31、8.18和7.57。因此,这些新的吡唑并吡啶衍生物代表高亲和力的腺苷A1受体选择性药物,与基于黄嘌呤的拮抗剂相反,它们对人,大鼠,小鼠和豚鼠脑膜中的[3H] -DPCPX结合位点具有相似的亲和力。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号