A Novel Partial Agonist of the A1 -Adenosine Receptor and Evidence of Receptor Homogeneity in Adipocytes

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Abstract
This study characterizes the receptor binding and functional effects of CVT-3619 [2-{6-[((1R,2R)-2-hydroxycyclopentyl)-amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]-oxolane-3,4-diol], a novel N6-5′ -substituted adenosine analog and A1 -adenosine receptor (A AdoR) agonist, on rat epididymal and inguinal adipocytes and on the isolated heart and compares these effects with those caused by the full agonist N6 -cyclopentyladenosine (CPA). In addition, the hypothesis that adipocyte A1AdoR are a heterogeneous population with regard to their affinities for ligands was tested. CVT-3619 was 10–100-fold selective for A1AdoR versus other AdoR and bound to adipocyte membranes with high (KH = 14 nM) and low (K = 5.4 μM) affinities. CVT-3619 reduced cyclic AMP content and release of nonesterified fatty acids from epididymal adipocytes with IC50 values of 6 and 44 nM, respectively. CVT-3619 was a partial agonist relative to CPA to reduce lipolysis in epididymal and inguinal adipocytes. CVT-3619 did not change atrial rate in rat heart and caused a small (6-ms) prolongation of the stimu-lus-to-His bundle interval without causing atrioventricular block in guinea pig heart (effects mediated by A1AdoR), whereas CPA caused atrioventricular block and near cessation of atrial electrical activity. CVT-3619 increased coronary conductance (effect mediated by A2AAdoR) only at concentrations ≥10 μM. Rat epididymal adipocyte A1AdoR had similar affinities for the antagonist 8-cyclopentyl-1,3-dipropylxanthine in the presence of three dissimilar A AdoR agonists (2-chloro-N6 -cyclopentyladenosine, N6 -sulfophenyladenosine, and N-5′ -ethylcarboxamidoadenosine) as determined by Schild analysis. It was concluded that rat epididymal adipocyte A1AdoR are a homogeneous receptor population with regard to affinities for ligands and that CVT-3619 is a partial agonist with selectivity for A1AdoR and inhibition of lipolysis.