title: 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.
authors.affiliation: CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Fatholahi
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Xiang
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C510789:2-(6-((2-hydroxycyclopentyl)amino)purin-9-yl)-5-((2-fluorophenylthio)methyl)oxolane-3,4-diol; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D005230:Fatty Acids, Nonesterified; D000242:Cyclic AMP; D000241:Adenosine