title: Pyran Template Approach to the Design of Novel A3Adenosine Receptor Antagonists.
abstract: [Table: see text] A3adenosine 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 A3adenosine 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 A3receptors 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 A3receptors were 6-methyl and 6-phenyl analogs,3a(MRS 1704) and4a(MRS 1705), respectively, of 3,5-diethyl 2-methyl-4-phenyl-4H-pyran-3,5-dicarboxylate, which had Kivalues of 381 and 583 nM, respectively. These two derivatives were selective for human A3receptors vs. rat brain A1receptors by 57-fold and 24-fold, respectively. These derivatives were inactive in binding at rat brain A2Areceptors, and at recombinant human A2Breceptors displayed Kivalues of 17.3 and 23.2 μM, respectively. The selectivity, but not affinity, of the pyran derivatives in binding to the A3receptor subtype was generally enhanced vs. the corresponding DHP derivatives.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: An-Hu
authors.initials: AH
authors.lastname: Li
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Xiao-Duo
authors.initials: XD
authors.lastname: Ji
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Hak Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Neli
authors.initials: N
authors.lastname: Melman
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
keywords: G protein-coupled receptors; purines; radioligand binding; structure–activity relationships; template