Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of many other members of group A G proteincoupled receptors, detailed qualitative and quantitative structure-activity relationships (SARs) were recently constructed for several of the subtypes. Agonists selective for P2Y 1 , P2Y 2 , and P2Y 6 receptors and nucleotide antagonists selective for P2Y 1 and P2Y 12 receptors are now known. Selective nonnucleotide antagonists were reported for P2Y 1 , P2Y 2 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 receptors. At the P2Y 1 and P2Y 12 receptors, nucleotide agonists (5′-diphosphate derivatives) were converted into antagonists of nanomolar affinity by altering the phosphate moieties, with a focus particularly on the ribose conformation and substitution pattern. Nucleotide analogues with conformationally constrained ribose-like rings were introduced as selective receptor probes for P2Y 1 and P2Y 6 receptors. Screening chemically diverse compound libraries has begun to yield new lead compounds for the development of P2Y receptor antagonists, such as competitive P2Y 12 receptor antagonists with antithrombotic activity. Selective agonists for the P2Y 4 , P2Y 11 , and P2Y 13 receptors and selective antagonists for P2Y 4 and P2Y 14 receptors have not yet been identified. The P2Y 14 receptor appears to be the most restrictive of the class with respect to modification of the nucleobase, ribose, and phosphate moieties. The continuing process of ligand design for the P2Y receptors will aid in the identification of new clinical targets.

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y 2 , P2Y 4 , and P2Y 6 receptors. The 2-thio modification, found previously to enhance P2Y 2 receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y 2 receptor, in the form of Up 4 -sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include: 9, α,β-methylene-UDP, a P2Y 6 receptor agonist; 30, Up 4 -phenyl ester and 34, Up 4 -[1]glucose, selective P2Y 2 receptor agonists; 43, the 2-thio analogue of INS37217 (P 1 -(uridine 5′)-P 4 -(2′-deoxycytidine 5′) tetraphosphate), a potent and selective P2Y 2 receptor agonist.

We have prepared 5′-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0]hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A 3 AR. The H-bonding ability of a group of 9-riboside derivatives containing a 5′-uronamide moiety was reduced by modification of the NH, however these derivatives did not display the desired activity as selective A 3 AR antagonists, as occurs with 5′-N,Ndimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 4′-hydroxymethyl group were highly potent and selective antagonists of the human A 3 AR. The compounds were synthesized from D-ribose using a reductive free radical decarboxylation of a 5′-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A 3 AR agonists. Compounds 33b -39b (N 6 -3-halobenzyl and related arylalkyl derivatives) were potent A 3 AR antagonists with binding K i values of 0.7 − 1.4 nM. In a functional assay of [ 35 S]GTPγS binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a K B of 8.9 nM. Thus, a highly potent and selective series of A 3 AR antagonists has been described.