N6-环戊基腺苷（CPA）的脱氧核糖类似物：体内腺苷A1受体的部分激动剂。

Deoxyribose analogues of N6-cyclopentyladenosine (CPA): partial agonists at the adenosine A1 receptor in vivo.

作者信息

Mathôt R A, Van der Wenden E M, Soudijn W, IJzerman A P, Danhof M

机构信息

Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratory, The Netherlands.

出版信息

Br J Pharmacol. 1995 Oct;116(3):1957-64. doi: 10.1111/j.1476-5381.1995.tb16398.x.

DOI:10.1111/j.1476-5381.1995.tb16398.x

PMID:8640332

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1908942/

Abstract

The purpose of the present study was to quantify the cardiovascular effects of the 2'-, 3'-, 5'-deoxyribose analogues of the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA) in vivo. The blood concentration-effect relationships of the compounds were assessed in individual rats and correlated to their receptor binding characteristics. 2. The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous infusion of 0.80 mg kg (-1) (63 micromol kg(-1)of 2' dCPA. The heart rate (HR) and mean arterial blood pressure (MAP) were monitored continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentration. 3. The relationship between blood concentrations and the reductions in both heart rate and blood pressure were described according to the sigmoidal Emax model. For the bradycardiac effect, the potencies based on free drug concentrations (EC50,u) of 5'dCPA, 3'dCPA, 2'dCPAin blood were 5.9 +/- 1.7, 18 +/- 4 and 260 +/- 70 ng ml (-1) (19 +/- 6, 56 +/- 11 and 830 +/- 210 nM), respectively, and correlated well with the adenosine A1 receptor affinity in vitro. The Emax value of 2'dCPA was significantly less than those of the other compounds, suggesting that this compound may be regarded as a partial agonist when compared to the other analogues. The rank order of the maximal reduction in heart rate of the compounds corresponded well with the order of the GTP-shifts, as determined in vitro. 4. It is concluded that deoxyribose derivatives of CPA may be partial agonists for the adenosine A1 receptor and may serve as tools for further investigation of adenosine receptor partial agonism in vivo.

摘要

本研究的目的是在体内定量选择性腺苷A1受体激动剂N6 - 环戊基腺苷（CPA）的2' -、3' -、5' - 脱氧核糖类似物对心血管的影响。在个体大鼠中评估了这些化合物的血药浓度 - 效应关系，并将其与它们的受体结合特性相关联。2. 在单次静脉输注0.80 mg·kg⁻¹（63 μmol·kg⁻¹）的2' - dCPA后，测定了这些化合物的药代动力学和药效学。在实验过程中持续监测心率（HR）和平均动脉血压（MAP），并采集系列动脉血样本用于药物浓度分析。3. 根据S形Emax模型描述了血药浓度与心率和血压降低之间的关系。对于心动过缓效应，基于血中5'dCPA、3'dCPA、2'dCPA的游离药物浓度（EC50,u）的效价分别为5.9±1.7、18±4和260±70 ng·ml⁻¹（19±6、56±11和830±210 nM），并且与体外腺苷A1受体亲和力良好相关。2'dCPA的Emax值显著低于其他化合物，表明与其他类似物相比，该化合物可能被视为部分激动剂。这些化合物使心率最大降低的顺序与体外测定的GTP位移顺序良好对应。4. 结论是，CPA的脱氧核糖衍生物可能是腺苷A1受体的部分激动剂，并可作为进一步研究体内腺苷受体部分激动作用的工具。