Search for New Purine- and Ribose-Modified Adenosine Analogs as Selective Agonists and Antagonists at Adenosine Receptors (original) (raw)

1995, Journal of Medicinal Chemistry

The binding affinities at rat AI, Aza, and & adenosine receptors of a wide range of derivatives of adenosine have been determined. Sites of modification include the purine moiety (1-, 3-, and 7-deaza; halo, alkyne, and amino substitutions a t the 2-and 8-positions; and NG-CHzring, -hydrazine, and -hydroxylamine) and the ribose moiety (2'-, 3'-, and 5'-deoxy; 2'-and 3'-0-methyl; 2'-deoxy 2'-fluoro; 6'4hio; 5'-uronamide; carbocyclic; 4'or 3'-methyl; and inversion of configuration). (-)-and (+)-5'-Noraristeromycin were 48-and 21-fold selective, respectively, for A2, vs A1 receptors. 2-Chloro-6'-thioadenosine displayed a K i value of 20 nM at Az, receptors (15-fold selective vs AI). 2-Chloroadenin-9-yl(~-~-2'-deoxy-6'-thiolyxofuranoside) displayed a Ki value of 8 pM at A1 receptors and appeared to be a n antagonist, on the basis of the absence of a GTP-induced shift in binding vs a radiolabeled antagonist (8-cyclopentyl-1,3-dipropylxanthine). 2-Chloro-2'-deoxyadenosine and 2-chloroadenin-9-yl(~-~-6'-thioarabinoside) were putative partial agonists at A1 receptors, with K i values of 7.4 and 5.4 pM, respectively. The Aza selective agonist 2-(1-hexynyl)-5'-(N-ethylcarbamoyl)adenosine displayed a K i value of 26 nM a t & receptors. The <-methyl substitution of adenosine was poorly tolerated, yet when combined with other favorable modifications, potency was restored. Thus, NG-benzyl-4'methyladenosine-5'-(N-methyluronamide) displayed a Ki value of 604 nM a t & receptors and was 103-and 88-fold selective vs A1 and Aga receptors, respectively. This compound was a full agonist in the &-mediated inhibition of adenylate cyclase in transfected CHO cells. The carbocyclic analogue of NG-(3-iodobenzyl)adenosine-5'-(N-methyluronamide) was 2-fold selective