Structure-activity relationships of thiazole and thiadiazole derivatives as potent and selective human adenosine A3 receptor antagonists.
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.
Jung
Kwan-Young
KY
Laboratory of Drug Discovery, Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
Kim
Soo-Kyung
SK
Gao
Zhan-Guo
ZG
Gross
Ariel S
AS
Melman
Neli
N
Jacobson
Kenneth A
KA
Kim
Yong-Chul
YC
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*
D058918:Adenosine A3 Receptor Antagonists; D043684:Receptor, Adenosine A3; D013844:Thiazoles; D000242:Cyclic AMP