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.
Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville 37232.
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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