Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions.
The effects of 8-phenyl and 8-cycloalkyl substituents on the activity of theophylline, caffeine, 1,3-dipropylxanthine, 1,3-dipropyl-7-methylxanthine, 3-propylxanthine, and 1-propylxanthine at A1 adenosine receptors of rat brain and fat cells and at A2 adenosine receptors of rat pheochromocytoma PC12 cells and human platelets are compared. An 8-phenyl substituent has little effect on the activity of caffeine or 1,3-dipropyl-7-methylxanthine at adenosine receptors, while markedly increasing activity of theophylline, 1,3-dipropylxanthine, 1-isoamyl-3-isobutylxanthine, 1-methylxanthine, and 3-propylxanthine. 8-Phenyl-1-propylxanthine is potent (Ki = 20-70 nM) at all receptors. A p-carboxy or p-sulfo substituent, which is introduced on the 8-phenyl ring to increase water solubility, in most cases decreases the activity and selectivity for the A1 receptor. Among the 8-p-sulfo analogues, only 8-(p-sulfophenyl)theophylline and 1,3-dipropyl-8-(p-sulfophenyl)xanthine are selective for the A1 receptors. 8-p-Sulfophenyl derivatives of caffeine, 1,3-dipropyl-7-methylxanthine, and 3-propylxanthine are somewhat selective for the A2 receptors. 8-Cycloalkyl substituents (cyclopentyl, cyclohexyl) markedly increase activity of caffeine and 1,3-dipropyl-7-methylxanthine at the A2 receptor. 8-Cyclohexylcaffeine is potent (Ki = 190 nM) and very selective for the human platelet A2 receptors, but is not as selective for the rat PC12 cell A2 receptor. Such A2 selectivity is in contrast to the marked A1 selectivity of 8-cycloalkyltheophyllines and 8-cycloalkyl-1,3-dipropulxanthines. The apparent selectivity of certain xanthines is dependent on the assay systems that are compared.
Shamim
M T
MT
Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
Ukena
D
D
Padgett
W L
WL
Daly
J W
JW
D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D015394:Molecular Structure; D010660:Phenylisopropyladenosine / Q000378:metabolism; D010673:Pheochromocytoma / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000494:pharmacology*
D011983:Receptors, Purinergic; D014970:Xanthines; C059952:1-propylxanthine; D010660:Phenylisopropyladenosine; C059953:1,3-dipropyl-7-methylxanthine; D002110:Caffeine; D013806:Theophylline; C034347:enprofylline; D000262:Adenylyl Cyclases; C046489:1,3-dipropylxanthine