Structure-activity relationships of 8-cycloalkyl-1,3-dipropylxanthines as antagonists of adenosine receptors.
8-Substituted xanthines currently represent the most potent class of adenosine-receptor antagonists. A series of 8-substituted 1,3-dipropylxanthines was prepared and their potency as antagonists of A1 and A2 adenosine receptors of human platelets and rat adipocytes, respectively, were determined. No agents studied were as potent as 8-cyclopentyl-1,3-dipropylxanthine as antagonists of the A1 adenosine receptor, but 8-(2-methylcyclopropyl)-1,3-dipropylxanthine was at least 1000-fold more potent as an antagonist of A1 than of A2 adenosine receptors. While most substitutions on the 8-cycloalkyl moiety caused decreased potency to inhibit both A1 and A2 adenosine receptors, 8-[trans-4-(acetamidomethyl)cyclohexyl]-1,3-dipropylxanthine was nearly equipotent as an antagonist of the two receptors and appeared to be the most potent antagonist of A2 adenosine receptors reported to date.
Katsushima
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T
Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville 37232.
Nieves
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Wells
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JN
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000097:blood; D000273:Adipose Tissue / Q000201:enzymology; D000478:Alkylation; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D002462:Cell Membrane / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D015394:Molecular Structure; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D007202:Indicators and Reagents; D011983:Receptors, Purinergic; D014970:Xanthines; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine