DEOXYRIBOSE ANALOGS OF N-6-CYCLOPENTYLADENOSINE (CPA) - PARTIAL AGONISTS AT THE ADENOSINE A(1) RECEPTOR IN-VIVO

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 At 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 mu mol kg(-1)) of 5'dCPA, 1.2 mg kg(-1) (3.8 mu mol kg(-1)) of 3'dCPA or 20 mg kg(-1) (63 mu mol 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 Al 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 Al receptor and may serve as tools for further investigation of adenosine receptor partial agonism in vivo.