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

Recent approaches to the design of selective agonists and antagonists at ad enosine (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 (m c) modification, to constrain the ring in a conformation that was favored i n binding to ARs or P2Y receptors. (N)-mc analogs of various N-6-substitute d adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which t he parent compounds are potent agonists at either A(1) or A(3)ARs, respecti vely, retained high receptor affinity and selectivity. For nucleotides acti ng as P2Y(1) 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 5 2 nM. Other ribose substitutions possible in P2Y1 receptor antagonists were 4- and 6-membered rings and acyclic derivatives. High affinity for the A(2 B)AR 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, K-i value 1.97 nM) was 205-, 255-, and 289-fold sele ctive for the human A(2B)ARS vs. human A(1)/A(2A)/A(3) 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 A(3)AR as well as the hum an A(3)AR. Chemical libraries were screened computationally and using bindi ng assays to identify novel AR antagonists. Molecular modeling of ARs and P 2Y receptors provided hypotheses for ligand docking. Drug Dev. Res. 52:178- 186, 2001. Published 2001 Wiley-Liss, Inc.