CHARACTERIZATION OF N-6-(5'-ENDOHYDROXY-ENDONORBORNYL)-9-METHYLADENINE (WRC-0571), A HIGHLY POTENT AND SELECTIVE, NONXANTHINE ANTAGONIST OFA(1) ADENOSINE RECEPTORS

Previous studies in our laboratory identified N-6-endonorbornyl-9-meth yladenine (N-0861) as a highly selective (100-fold) A(1)-adenosine rec eptor antagonist (K-B = 500 nM). However, its moderate potency limits the degree of A(1)-receptor blockade that can be achieved by systemica lly administered N-0861. Structure activity studies were undertaken to invent a compound that had greater affinity for the A(1)-adenosine re ceptors than N-0861. 8-N-methylisopropylamino-N-6-5'-endohydroxy-N-086 1 (WRC-0571) inhibited [H-3]-N-6-cyclohexyladenosine (CHA) binding to guinea pig A(1)-receptors with a K-l value of 1.1 nM. WRC-0571 was 200 -fold less potent at inhibiting [H-3]-5'-N-ethylcarboxamidoadenosine b inding to bovine A,, receptors (K-l = 234 nM). WRC-0571 also inhibited the binding of radioligands to cloned human A(1), A(2a) and A(3) aden osine receptors with affinities of 1.7, 105 and 7940 nM, respectively. Thus in human adenosine receptors, WRC-0571 is 62-fold selective for the A(1) vs. A(2a) and 4670-fold selective for the A(1) vs. A(3) recep tors; WRC-0571 is therefore the most A, vs. A, selective compound yet described. In guinea pig isolated atria, WRC-0571 antagonized the A(1) -mediated negative inotropic responses to 5'-N-ethylcarboxamidoadenosi ne (NECA) with a K-B of 3.4 nM. WRC-0571 was more than 2500-fold less potent at antagonizing NECA-induced A(2b)-mediated relaxation in guine a pig aorta. In anesthetized rats WRC-0571 antagonized adenosine-induc ed bradycardia at concentrations as low as 1 nmol/kg but failed to ant agonize A(2)-mediated hindquarter vasodilation at concentrations up to 10,000 nmol/kg. WRC-0571 is orally active at concentrations as low as 0.3 mu mol/kg. WRC-0571 is therefore a highly potent, highly selectiv e antagonist of A,adenosine receptors both in vitro and in vivo.