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

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 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.
AuthorsMarjan Fatholahi, Yiwen Xiang, Yuzhi Wu, Yuan Li, Lin Wu, Arvinder K Dhalla, Luiz Belardinelli, John C Shryock
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 317 Issue 2 Pg. 676-84 (May 2006) ISSN: 0022-3565 [Print] United States
PMID16410404 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 2-(6-((2-hydroxycyclopentyl)amino)purin-9-yl)-5-((2-fluorophenylthio)methyl)oxolane-3,4-diol
  • Adenosine A1 Receptor Agonists
  • Adenosine A1 Receptor Antagonists
  • Fatty Acids, Nonesterified
  • Cyclic AMP
  • Adenosine
Topics
  • Adenosine (analogs & derivatives, pharmacology)
  • Adenosine A1 Receptor Agonists
  • Adenosine A1 Receptor Antagonists
  • Adipocytes (drug effects, metabolism)
  • Animals
  • Cell Membrane (drug effects, 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

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