Synthesis, Biological Activity, and Molecular Modeling of Ribose-Modified Deoxyadenosine Bisphosphate Analogues as P2Y1 Receptor Ligands

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Abstract
The structure−activity relationships of adenosine-3‘,5‘-bisphosphates as P2Y1 receptor antagonists have been explored, revealing the potency-enhancing effects of the N6-methyl group and the ability to substitute the ribose moiety (Nandanan et al. J. Med. Chem. 1999, 42, 1625−1638). We have introduced constrained carbocyclic rings (to explore the role of sugar puckering), non-glycosyl bonds to the adenine moiety, and a phosphate group shift. The biological activity of each analogue at P2Y1 receptors was characterized by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit its stimulation elicited by 30 nM 2-methylthioadenosine-5‘-diphosphate (antagonist effect). Addition of the N6-methyl group in several cases converted pure agonists to antagonists. A carbocyclic N6-methyl-2‘-deoxyadenosine bisphosphate analogue was a pure P2Y1 receptor antagonist and equipotent to the ribose analogue (MRS 2179). In the series of ring-constrained methanocarba derivatives where a fused cyclopropane moiety constrained the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle, the 6-NH2 (N)-analogue was a pure agonist of EC50 155 nM and 86-fold more potent than the corresponding (S)-isomer. The 2-chloro-N6-methyl-(N)-methanocarba analogue was an antagonist of IC50 51.6 nM. Thus, the ribose ring (N)-conformation appeared to be favored in recognition at P2Y1 receptors. A cyclobutyl analogue was an antagonist with IC50 of 805 nM, while morpholine ring-containing analogues were nearly inactive. Anhydrohexitol ring-modified bisphosphate derivatives displayed micromolar potency as agonists (6-NH2) or antagonists (N6-methyl). A molecular model of the energy-minimized structures of the potent antagonists suggested that the two phosphate groups may occupy common regions. The (N)- and (S)-methanocarba agonist analogues were docked into the putative binding site of the previously reported P2Y1 receptor model.

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