Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine.
Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine.
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变构增强剂 PD 81,723 通过新机制发挥作用，增强腺苷的心脏作用。
DOI：
10.1161/01.res.75.6.961
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发表时间：
1994
影响因子：
20.1
通讯作者：
Belardinelli,L
中科院分区：
文献类型：
--
作者：
Kollias-Baker,C;Ruble,J;Dennis,D;Bruns,RF;Linden,J;Belardinelli,L
2-氨基-3-苯甲酰基噻吩衍生物PD 81，723是一种与脑A1腺苷受体结合的激动剂的变构增强剂。本研究的一个目的是表征和对比PD 81，723对腺苷和非代谢性和非选择性N6-（3-戊基）腺苷衍生物的A1受体介导的负性传导性和A2 a受体介导的血管舒张作用的影响。第二个目的是确定PD 81，723的作用机制。在豚鼠离体心脏中，PD 81，723以浓度依赖性方式增强腺苷和N6-（3-戊基）腺苷衍生物诱导的刺激-希氏束（S-H）间期延长。PD 81，723（30 mumol/L）使腺苷延长S-H间期的EC 50值降低9倍，从7.4 +/- 1.2降至0.8 +/- 0.1 mumol/L，但未增加心脏流出液中腺苷的含量。PD 81，723（30 mumol/L）使A1激动剂[3 H]环己基腺苷（[3 H]CHA）与人心房和豚鼠心房和脑细胞膜的特异性结合分别增加38%、78%和300%。PD 81，723还使高亲和力结合状态下的A1受体分数平均增加56 +/-13%。PD 81，723（10 μ mol/L）存在时，[3 H]CHA从豚鼠脑细胞膜上的解离速率从0.55 +/- 0.01/min降低至0.35 +/- 0.01/min。PD 81，723未改变A1拮抗剂[3 H]环戊基二丙基黄嘌呤与豚鼠脑细胞膜的结合。5 '-鸟苷酰亚氨基二磷酸降低[3 H]CHA与豚鼠心肌和脑细胞膜特异性结合的IC 50值分别从不存在PD 81，723时的1.5 +/- 0.2和2.0 +/- 0.2 μ mol/L增加至存在PD 81时的10 +/- 3.3和18 +/- 0.5 μ mol/L，723（30 μ mol/L）。PD 81，723不增强N6-（3-戊基）腺苷衍生物的冠状血管舒张作用。存在PD 81，723时，A2 a激动剂[3 H]CGS 21680与脑细胞膜的特异性结合以及核苷转运蛋白配体[3 H]硝基苄基硫代肌苷与心脏细胞膜的特异性结合未发生变化。结果表明，PD 81，723通过在激动剂存在下稳定受体-G蛋白相互作用，特异性增强腺苷对A1受体的作用。
The 2-amino-3-benzoylthiophene derivative PD 81,723 is an allosteric enhancer of agonist binding to brain A1 adenosine receptors. One aim of this study was to characterize and contrast the effects of PD 81,723 on the A1 receptor-mediated negative dromotropic and A2a receptor-mediated vasodilatory actions of adenosine and of a nonmetabolizable and unselective N6-(3-pentyl)adenosine derivative. A second aim was to determine the mechanism of action of PD 81,723. In guinea pig isolated hearts, PD 81,723 potentiated the adenosine and the N6-(3-pentyl)adenosine derivative-induced prolongations of the stimulus-to-His bundle (S-H) interval in a concentration-dependent manner. PD 81,723 (30 mumol/L) decreased the EC50 value for adenosine to prolong the S-H interval by ninefold from 7.4 +/- 1.2 to 0.8 +/- 0.1 mumol/L but did not increase the content of adenosine in cardiac effluent. PD 81,723 (30 mumol/L) increased the specific binding of the A1 agonist [3H]cyclohexyladenosine ([3H]CHA) to human atrial and guinea pig atrial and brain membranes by 38%, 78%, and 300%, respectively. PD 81,723 also increased the fraction of A1 receptors in the high-affinity binding state by an average of 56 +/- 13%. The dissociation rate of [3H]CHA from guinea pig brain membranes was decreased in the presence of PD 81,723 (10 mumol/L) from 0.55 +/- 0.01/min to 0.35 +/- 0.01/min. PD 81,723 did not alter the binding of the A1 antagonist [3H]cyclopentyldipropylxanthine to guinea pig brain membranes. The IC50 values for 5'-guanylylimidodiphosphate to reduce specific binding of [3H]CHA to guinea pig cardiac and brain membranes were increased from 1.5 +/- 0.2 and 2.0 +/- 0.2 mumol/L in the absence of PD 81,723 to 10 +/- 3.3 and 18 +/- 0.5 mumol/L, respectively, in the presence of PD 81,723 (30 mumol/L). PD 81,723 did not potentiate the coronary vasodilatory actions of the N6-(3-pentyl)adenosine derivative. Specific binding of the A2a agonist [3H]CGS 21680 to brain membranes and the nucleoside transporter ligand [3H]nitrobenzylthioinosine to cardiac membranes was unchanged in the presence of PD 81,723. The results suggest that PD 81,723 specifically potentiates the action of adenosine on A1 receptors by stabilizing receptor-G protein interactions in the presence of agonists.
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影响因子：
3.8
作者：
J. Linden;A. Tucker;A. Robeva;S. G. Graber;R. Munshi
通讯作者：
R. Munshi
使用腺苷诊断和治疗心律失常的电生理学基础。
影响因子：
--
作者：
Luiz Belardinelli;B. Lerman
通讯作者：
B. Lerman
DOI：
10.1080/07328319108047235
发表时间：
1991
期刊：
Nucleosides, Nucleotides & Nucleic Acids
影响因子：
--
作者：
H. Belle;P. Janssen
通讯作者：
P. Janssen
豚鼠大脑中的高亲和力右美沙芬结合位点：进一步表征和变构相互作用。
DOI：
--
发表时间：
1988
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Musacchio,JM;Klein,M;Santiago,LJ
通讯作者：
Santiago,LJ
影响因子：
5.8
作者：
HERNANDEZMUNOZ, R;GLENDER, W;DESANCHEZ, VC
通讯作者：
DESANCHEZ, VC