title: Structure-activity relationships of thiazole and thiadiazole derivatives as potent and selective human adenosine A3 receptor antagonists.
abstract: 4-(4-Methoxyphenyl)-2-aminothiazole and 3-(4-methoxyphenyl)-5-aminothiadiazole derivatives have been synthesized and evaluated as selective antagonists for human adenosine A3 receptors. A methoxy group in the 4-position of the phenyl ring and N-acetyl or propionyl substitutions of the aminothiazole and aminothiadiazole templates displayed great increases of binding affinity and selectivity for human adenosine A3 receptors. The most potent A3 antagonist of the present series, N-[3-(4-methoxy-phenyl)-[1,2,4]thiadiazol-5-yl]-acetamide (39) exhibiting a Ki value of 0.79 nM at human adenosine A3 receptors, showed antagonistic property in a functional assay of cAMP biosynthesis involved in one of the signal transduction pathways of adenosine A3 receptors. Molecular modeling study of conformation search and receptor docking experiments to investigate the dramatic differences of binding affinities between two regioisomers of thiadiazole analogues, (39) and (42), suggested possible binding mechanisms in the binding pockets of adenosine receptors.
authors.affiliation: Laboratory of Drug Discovery, Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors.forename: Kwan-Young
authors.initials: KY
authors.lastname: Jung
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Ariel S
authors.initials: AS
authors.lastname: Gross
authors.forename: Neli
authors.initials: N
authors.lastname: Melman
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D058918:Adenosine A3 Receptor Antagonists; D001665:Binding Sites; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D043684:Receptor, Adenosine A3; D013844:Thiazoles; D000242:Cyclic AMP