A novel partial agonist of the A(1)-adenosine receptor and evidence of receptor homogeneity in adipocytes

• Published in: The Journal of pharmacology and experimental therapeutics 2006-05, Vol.317 (2), p.676-684
• Main Authors: Fatholahi, Marjan, Xiang, Yiwen, Wu, Yuzhi, Li, Yuan, Wu, Lin, Dhalla, Arvinder K, Belardinelli, Luiz, Shryock, John C
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Adipocytes - drug effects; Adipocytes - metabolism; Animals; Cell Membrane - drug effects; Cell Membrane - metabolism; Cells, Cultured; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified - metabolism; Female; Guinea Pigs; Heart Conduction System - drug effects; Hemodynamics - drug effects; Male; Myocardium - metabolism; Protein Binding; Radioligand Assay; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3565
• DOI: 10.1124/jpet.105.099119

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 N(6)-5' -substituted adenosine analog and A(1) -adenosine receptor (A(1) AdoR) agonist, on rat epididymal and inguinal adipocytes and on the isolated heart and compares these effects with those caused by the full agonist N(6) -cyclopentyladenosine (CPA). In addition, the hypothesis that adipocyte A(1)AdoR are a heterogeneous population with regard to their affinities for ligands was tested. CVT-3619 was 10-100-fold selective for A(1)AdoR versus other AdoR and bound to adipocyte membranes with high (K(H) = 14 nM) and low (K = 5.4 microM) affinities. CVT-3619 reduced cyclic AMP content and release of nonesterified fatty acids from epididymal adipocytes with IC(50) 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 stimulus-to-His bundle interval without causing atrioventricular block in guinea pig heart (effects mediated by A(1)AdoR), whereas CPA caused atrioventricular block and near cessation of atrial electrical activity. CVT-3619 increased coronary conductance (effect mediated by A(2A)AdoR) only at concentrations > or =10 microM. Rat epididymal adipocyte A(1)AdoR had similar affinities for the antagonist 8-cyclopentyl-1,3-dipropylxanthine in the presence of three dissimilar A AdoR agonists (2-chloro-N(6) -cyclopentyladenosine, N(6) -sulfophenyladenosine, and N-5' -ethylcarboxamidoadenosine) as determined by Schild analysis. It was concluded that rat epididymal adipocyte A(1)AdoR are a homogeneous receptor population with regard to affinities for ligands and that CVT-3619 is a partial agonist with selectivity for A(1)AdoR and inhibition of lipolysis.