ALLOSTERIC ENHANCER PD-81,723 ACTS BY NOVEL MECHANISM TO POTENTIATE CARDIAC ACTIONS OF ADENOSINE

The 2-amino-3-benzoylthiophene derivative PD 81,723 is an allosteric e nhancer of agonist binding to brain A(1) adenosine receptors. One aim of this study was to characterize and contrast the effects of PD 81,72 3 on the A(1) receptor-mediated negative dromotropic and A(1) receptor -mediated vasodilatory actions of adenosine and of a nonmetabolizable and unselective N-6-(3-pentyl)adenosine derivative. A second aim was t o determine the mechanism of action of PD 81,723. In guinea pig isolat ed hearts, PD 81,723 potentiated the adenosine and the N-6-(3-pentyl)a denosine derivative-induced prolongations of the stimulus-to-His bundl e (S-H) interval in a concentration-dependent manner. PD 81,723 (30 mu mol/L) decreased the EC(50) value for adenosine to prolong the S-H in terval by ninefold from 7.4 +/- 1.2 to 0.8 +/- 0.1 mu mol/L but did no t increase the content of adenosine in cardiac effluent. PD 81,723 (30 mu mol/L) increased the specific binding of the A(1) agonist [H-3]cyc lohexyladenosine ([H-3]CHA) to human atrial and guinea pig atrial and brain membranes by 38%, 78%, and 300%, respectively. PD 81,723 also in creased the fraction of A(1) receptors in the high-affinity binding st ate by an average of 56 +/- 13%. The dissociation rate of [H-3]CKA fro m guinea pig brain membranes was decreased in the presence of PD 81,72 3 (10 mu mol/L) from 0.55 +/- 0.01/min to 0.35 +/- 0.01/min. PD 81,723 did not alter the binding of the A(1) antagonist [H-3]cyclopentyldipr opylxanthine to guinea pig brain membranes. The IC50 values for 5'-gua nylylimidodiphosphate to reduce specific binding of [H-3]CKA to guinea pig cardiac and brain membranes were increased from 1.5 +/- 0.2 and 2 .0 +/- 0.2 mu mol/L in the absence of PD 81,723 to 10 +/- 3.3 and 18 /- 0.5 mu mol/L, respectively, in the presence of PD 81,723 (30 mu mol /L). PD 81,723 did not potentiate the coronary vasodilatory actions of the N-6-(3-pentyl)adenosine derivative. Specific binding of the A(2a) agonist [H-3]CGS 21680 to brain membranes and the nucleoside transpor ter ligand [H-3]nitrobenzylthioinosine to cardiac membranes was unchan ged in the presence of PD 81,723. The results suggest that PD 81,723 s pecifically potentiates the action of adenosine on A(1) receptors by s tabilizing receptor-G protein interactions in the presence of agonists .