A 3 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 A 3 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 A 3 receptors expressed in CHO cells was determined vs. binding of [ 125 I]AB-MECA (N 6 -(4-amino-3-iodobenzyl)-5β²-N-methylcarbamoyladenosine). There was no potency-enhancing effect, as was observed for DHPs, of 4-styryl, 4phenylethynyl, or 6-phenyl substitutions. The most potent ligands in this group in binding to human A 3 receptors were 6-methyl and 6-phenyl analogs, 3a (MRS 1704) and 4a (MRS 1705), respectively, of 3,5diethyl 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 A 3 receptors vs. rat brain A 1 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 Β΅M, respectively. The selectivity, but not affinity, of the pyran derivatives in binding to the A 3 receptor subtype was generally enhanced vs. the corresponding DHP derivatives.