7-Deaza-9-phenyladenines. A new class of adenosine receptor antagonists.
A series of twelve 7-deaza-9-phenyladenines and of related 9-aralkyl-, 9-alkyl-, and 9-alkenyl-analogs and of 7-deaza-9-phenylhypoxanthines inhibited binding of [3H]phenylisopropyladenosine to rat brain A1-adenosine receptors and antagonized activation of adenylate cyclase elicited by interaction of N-ethylcarboxamidoadenosine with A2-adenosine receptors in rat pheochromocytoma PC12 cell membranes. A subset of seven compounds, encompassing the range of major structural variations, antagonized inhibition of adenylate cyclase elicited by interaction of R-phenylisopropyladenosine with A1-adenosine receptors in rat fat cell membranes. 7-Deaza-9-phenyladenine had a Ki value of 3 microM at the brain A1-receptor and a KB value of 17 microM at the PC12 A2-receptor and was thus about 5-fold more potent than theophylline at the former and nearly equipotent with theophylline at the latter. It had a KB value of 4.6 microM at the fat cell A1-receptor. The presence of methyl groups at the 7- and 8-positions reduced activity at all receptors several fold. Aryl substituents in a series of 7-deaza-7,8-dimethyl-9-phenyladenines did not have major effects on affinities for the brain A1- or the PC12 cell A2-adenosine receptors. The absence of the 9-phenyl substituent in the 7,8-dimethyl series reduced activity several fold, while replacement with arylalkyl (-CH2C6H4F), alkyl (-(CH2)5CH3) or alkenyl (-CH2CH = CH2) substituents had only modest effects on potency at the brain A1-receptor and the PC12 cell A2-receptor. 7-Deaza-7,8-dimethylhypoxanthine was nearly equipotent to the analogous 7-deazaadenine at the brain and fat cell A1-receptors, but was several fold more potent than the analogous 7-deazaadenine at the A2-receptor. 7-Deaza-7,8-dimethyl-9-(2,4-dibromophenyl)hypoxanthine was less potent than the analogous 7-deazaadenine at both the brain A1- and the PC12 cell A2-adenosine receptors. 7-Deaza-9-phenyl-7,8-benzohypoxanthine was the most potent of the present series of antagonists and was somewhat selective for the A2-adenosine receptor with a Ki of 0.9 microM at the brain A1-receptor, a KB of 1.4 microM at the fat cell A1-receptor, and a KB of 0.2 microM at the A2-receptor.
Daly
J W
JW
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD 20892.
Padgett
W L
WL
Eger
K
K
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000037:antagonists & inhibitors*; D000818:Animals; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D066298:In Vitro Techniques; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects*; D013329:Structure-Activity Relationship
D007042:Hypoxanthines; D011983:Receptors, Purinergic; D019271:Hypoxanthine; D000225:Adenine; D000241:Adenosine