Pyran Template Approach to the Design of Novel A₃ Adenosine Receptor Antagonists

[Table: see text] A₃ adenosine receptor antagonists have potential as anti-inflammatory, anti-asthmatic, and anti-ischemic agents. We previously reported the preparation of chemical libraries of 1,4-dihydropyridine (DHP) and pyridine derivatives and identification of members having high affinity at A₃ adenosine receptors. These derivatives were synthesized through standard three-component condensation/oxidation reactions, which permitted versatile ring substitution at five positions, i.e., the central ring served as a molecular scaffold for structurally diverse substituents. We extended this template approach from the DHP series to chemically stable pyran derivatives, in which the ring NH is replaced by O and which is similarly derived from a stepwise reaction of three components. Since the orientation of substituent groups may be conformationally similar to the 1,4-DHPs, a direct comparison between the structure activity relationships of key derivatives in binding to adenosine receptors was carried out. Affinity at human A₃ receptors expressed in CHO cells was determined vs. binding of [¹²⁵I]AB-MECA (N⁶-(4-amino-3-iodobenzyl)-5'-N-methyl-carbamoyladenosine). There was no potency-enhancing effect, as was observed for DHPs, of 4-styryl, 4-phenylethynyl, or 6-phenyl substitutions. The most potent ligands in this group in binding to human A₃ receptors were 6-methyl and 6-phenyl analogs, 3a (MRS 1704) and 4a (MRS 1705), respectively, of 3,5-diethyl 2-methyl-4-phenyl-4H-pyran-3,5-dicarboxylate, which had K_i values of 381 and 583 nM, respectively. These two derivatives were selective for human A₃ receptors vs. rat brain A₁ receptors by 57-fold and 24-fold, respectively. These derivatives were inactive in binding at rat brain A_2A receptors, and at recombinant human A_2B receptors displayed K_i values of 17.3 and 23.2 microM, respectively. The selectivity, but not affinity, of the pyran derivatives in binding to the A₃ receptor subtype was generally enhanced vs. the corresponding DHP derivatives.