QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.099119v1 317/2/676    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fatholahi, M. Articles by Shryock, J. C. Search for Related Content PubMed PubMed Citation Articles by Fatholahi, M. Articles by Shryock, J. C.

ENDOCRINE AND DIABETES

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

CV Therapeutics, Inc., Palo Alto, California (M.F., Y.W., Y.L., L.W., A.K.D., L.B., J.C.S.); and Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida (Y.X., J.C.S.)

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 (K_H = 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 A_2AAdoR) 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.

Address correspondence to: Dr. John C. Shryock, 3172 Porter Drive, Palo Alto, CA 94304. E-mail: john.shryock{at}cvt.com

This article has been cited by other articles:

				A. K. Dhalla, M. Y. Wong, P. J. Voshol, L. Belardinelli, and G. M. Reaven A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1358 - E1363. [Abstract] [Full Text] [PDF]

				A. K. Dhalla, M. Santikul, M. Smith, M.-Y. Wong, J. C. Shryock, and L. Belardinelli Antilipolytic Activity of a Novel Partial A1 Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 327 - 333. [Abstract] [Full Text] [PDF]