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Deoxyribose analogues of N 6 ‐cyclopentyladenosine (CPA): partial agonists at the adenosine A 1 receptor in vivo
Author(s) -
Mathôt R.A.A.,
Wenden E.M.,
Soudijn W.,
IJzerman A.P.,
Danhof M.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb16398.x
Subject(s) - partial agonist , in vivo , agonist , adenosine , chemistry , pharmacokinetics , pharmacology , heart rate , receptor , endocrinology , medicine , blood pressure , biochemistry , biology , microbiology and biotechnology
1 The purpose of the present study was to quantify the cardiovascular effects of the 2′‐, 3′‐ and 5′‐deoxyribose analogues of the selective adenosine A 1 receptor agonist, N 6 ‐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 (2.5 μmol kg −1 ) of 5′dCPA, 1.2 mg kg −1 (3.8 μmol kg −1 ) of 3′dCPA or 20 mg kg −1 (63 μmol 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 E max model. For the bradycardiac effect, the potencies based on free drug concentrations (EC 50, u ) of 5′dCPA, 3′dCPA and 2′dCPA in 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 A 1 receptor affinity in vitro . The E max 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 A 1 receptor and may serve as tools for further investigation of adenosine receptor partial agonism in vivo .