7-Deaza-2-phenyladenines: structure-activity relationships of potent A1 selective adenosine receptor antagonists.
A series of derivatives of 7-deazapurines with varying substituents in the 2-, 6-, and 9-position was synthesized in an attempt to improve the adenosine receptor affinity and A1 or A2 selectivity. The adenosine receptor affinities were assessed by measuring the inhibition of [3H]-(R)-N6-(phenylisopropyl) adenosine (R-PIA) binding to rat brain A1 and inhibition of [3H]-5'-(N-ethylcarboxamido)adenosine (NECA) binding to rat striatum A2 adenosine receptors. A selected set of compounds representing the main structural variations was further examined in adenosine receptor coupled adenylate cyclase assays. All tested compounds antagonized the inhibition of adenylate cyclase elicited by interaction of R-PIA with A1 receptors in rat fat cell membranes and the activation of adenylate cyclase elicited by interaction of NECA with A2 receptors of pheochromocytoma PC12 cell membranes. The results indicate that 7-deazahypoxanthines have a potential for A2 selectivity, while all 7-deazaadenines are A1 selective. Introduction of a phenyl residue in the 2-position of 7-deazaadenines increases A1 activity tremendously. 2-(p-Chlorophenyl)-7,8-dimethyl-9-phenyl-7-deazaadenine (29) is potent and specific for the A1 receptors of rat brain (Ki = 122 nM), having no affinity for the A2 receptors of rat striatum. The compound has low activity at the A2 receptors of rat PC12 cell membranes where it appears to act as a noncompetitive inhibitor. A 1-phenylethyl substituent at the 9-position was found to be superior to a phenyl residue in terms of A1 affinity. The most potent A1 antagonist in the present series is the highly A1 selective (790-fold) (R)-7,8-dimethyl-2-phenyl-9-(1-phenylethyl)-7-deazaadenine (31, Ki = 4.7 nM), which is 30-35 times more potent at A1 receptors than its S enantiomer. The solubility of six of the potent 7-deaza-2-phenyladenines was determined by means of an A1 binding assay. Chloro substitution of the 2-phenyl ring appeared to improve the solubility as well as the solubility over A1 affinity ratio of 9-phenyl- and 9-(1-phenylethyl)-substituted 7-deazadenines.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
C E
CE
Müller
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Hide
J W
JW
Daly
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Rothenhäusler
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Eger
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D019830:Adenosine-5'-(N-ethylcarboxamide); D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003342:Corpus Striatum / Q000378:metabolism; D007042:Hypoxanthines / Q000737:chemistry; D066298:In Vitro Techniques; D010660:Phenylisopropyladenosine / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007042:Hypoxanthines; D011983:Receptors, Purinergic; D010660:Phenylisopropyladenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D000262:Adenylyl Cyclases; D000225:Adenine; D000241:Adenosine