(+ -)-N6-ENDONORBORNAN-2-YL-9-METHYLADENINE (N-0861) AND ITS ENANTIOMERS - SELECTIVE ANTAGONISTS OF ADENOSINE-A1-RECEPTORS IN GUINEA-PIG ISOLATED ATRIA/

Adenosine and its metabolically stable analog 5'-N-ethylcarboxamidoade nosine (NECA) induce negative inotropic, chronotropic and dromotropic actions in the heart through activation of A1-adenosine receptors and relaxation of vascular smooth muscle through activation of A2-adenosin e receptors. In vitro studies were carried out in order to determine t he potency of the antagonist (+/-)-N6-endonorbornan-2-yl-9-methyladeni ne (N-0861) and its two component enantiomers, WRC-0006(+) and WRC-000 7(-), at the Al receptors in the guinea pig atria and the A2 receptors in the guinea pig aorta. N-0861 competitively antagonized the negativ e inotropic responses induced by NECA in the electrically paced left a trium (pK(B) = 6.24) and the negative chronotropic responses induced b y NECA in the spontaneously beating right atrium (pK(B) = 6.29). WRC-0 007 was 4-fold more potent (pK(B) = 6.51) than WRC-0006 (pK(B) = 5.86) at antagonizing the A1-adenosine receptors in the guinea pig left atr ium. N-0861, WRC-0007 and WRC-0006 at high concentrations (> 3 x 10(-5 ) M) produced direct relaxations of the guinea pig aorta that masked t o a small extent the A2 receptor antagonism by these compounds. The af finities of the antagonists for the A2 receptor in the aorta were calc ulated using the method of pharmacological resultant analysis. N-0861 was 47-fold less potent at the A2 receptor (pK(B) = 4.57) than it was at the Al receptor. WRC-0006 was 2-fold more potent (pK(B) = 4.81) tha n WRC-0007 (pK(B) = 4.52) at the A2-adenosine receptor. N-0861 is, the refore, a moderately potent (pK(B) = 6.2) and selective (47-fold) anta gonist in vitro for the A1-adenosine receptors. Of the individual enan tiomers, WRC-0007 is a more potent (pK(B) = 6.5) A1 antagonist than is WRC-0006 (pK(B) = 5.9), and is also more A1 selective (98-fold vs. 11 -fold).