SEARCH FOR NEW PURINE-MODIFIED AND RIBOSE-MODIFIED ADENOSINE-ANALOGS AS SELECTIVE AGONISTS AND ANTAGONISTS AT ADENOSINE RECEPTORS

The binding affinities at rat A(1), A(2a), and A(3) adenosine receptor s of a wide range of derivatives of adenosine have been determined. Si tes of modification include the purine moiety (1-, 3-, and 7-deaza; ha lo, alkyne, and amino substitutions at the 2- and 8-positions; and N6( -)CH(2)-ring, -hydrazino, and -hydroxylamino) and the ribose moiety (2 '-, 3'-, and 5'-deoxy; 2'- and 3'-O-methyl;2'-deoxy 2'-fluoro;6'-thio; 5'-uronamide;carbocyclic;4'- or 3'-methyl; and inversion of configurat ion. (-)- and (+)-5'-Noraristeromycin were 48- and 21-fold selective, respectively, for A(2a), vs A(1) receptors. 2-Chloro-6'-thioadenosine displayed a K-i value of 20 nM at A(2a) receptors (15-fold selective v s A(1)). adenin-9-yl(beta-L-2'-deoxy-6'-thiolyxofuranoside) displayed a K-i value of 8 mu M at A(1) receptors and appeared to be an antagoni st, on the basis of the absence of a GTP-induced shift in binding vs a radiolabeled antagonist (8-cyclopentyl-1,3-dipropylxanthine). 2-Chlor o-2'-deoxyadenosine and 2-chloroadenin-9-yl(beta-D-6'-thioarabinoside) were putative partial agonists at A(1) receptors, with K-i values of 7.4 and 5.4 mu M, respectively. The A(2a) selective agonist 2-(1-hexyn yl)-5'-(N-ethylcarbamoyl)adenosine displayed a K-i value of 26 nM at A (3) receptors. The 4'-methyl substitution of adenosine was poorly tole rated, yet when combined with other favorable modifications, potency w as restored. Thus, -6-benzyl-4'methyladenosine-5'-(N-methyluronamide) displayed a K-i value of 604 nM at A(3) receptors and was 103- and 88- fold selective vs A(1) and A(2a) receptors, respectively. This compoun d was a full agonist in the A(3)-mediated inhibition of adenylate cycl ase in transfected CHO cells. The carbocyclic analogue of N-6-(3-iodob enzyl)adenosine-5'-(N-methyluronamide) was 2-fold selective for A(3) V S A(1) receptors and was nearly inactive at A(2a) receptors.