Probing adenosine and P2 receptors: Design of novel purines and nonpurines as selective ligands

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Abstract
Recent approaches to the design of selective agonists and antagonists at adenosine (AR) and P2 receptors include both modifying known receptor ligands and searching for structurally diverse antagonists. The ribose-like moiety of nucleoside/nucleotide derivatives was rigidified with a methanocarba (mc) modification, to constrain the ring in a conformation that was favored in binding to ARs or P2Y receptors. (N)-mc analogs of various N6-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A1 or A3ARs, respectively, retained high receptor affinity and selectivity. For nucleotides acting as P2Y1 receptor antagonists, the (N)-mc analog MRS 2279 ((1R,2S,4S,5S)-1-[(phosphato)methyl]-4-(2-chloro-6-methylaminopurin-9-yl) bicyclo [3.1.0]-hexane-2-phosphate) proved to be a selective antagonist, with an IC50 of 52 nM. Other ribose substitutions possible in P2Y1 receptor antagonists were 4- and 6-membered rings and acyclic derivatives. High affinity for the A2BAR was achieved through the formation of anilides and benzylamides of XCC (8-[4-[[[carboxy]methyl]oxy]phenyl]-1,3-dipropylxanthine). A p-cyanoaniline derivative (MRS 1754, Ki value 1.97 nM) was 205-, 255-, and 289-fold selective for the human A2BARs vs. human A1/A2A/A3 ARs, respectively. A template approach based on the pyridine family, i.e., 1,4-dihydropyridine nucleus and the corresponding 3,5-diacylpyridines, was used for the design of novel adenosine antagonists. The pyridine derivative MRS 1523 (5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate) was shown to be a selective antagonist at the rat A3AR as well as the human A3AR. Chemical libraries were screened computationally and using binding assays to identify novel AR antagonists. Molecular modeling of ARs and P2Y receptors provided hypotheses for ligand docking. Drug Dev. Res. 52:178-186, 2001.

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