title: 1,3-Dialkyl-8-(p-sulfophenyl)xanthines: potent water-soluble antagonists for A1- and A2-adenosine receptors.
abstract: A series of 8-(substituted phenyl) derivatives of theophylline and other 1,3-dialkylxanthines were evaluated for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Theophylline has a similar potency (Ki = 14 microM) at both A1 and A2 receptors. 8-Phenyltheophylline is 25-35-fold more potent as an adenosine receptor antagonist than theophylline, while 8-phenylcaffeine is only 2-3-fold more potent than caffeine. A p-hydroxyaryl substituent enhances the potency of 8-phenyltheophylline as an adenosine antagonist. p-Carboxy- and p-sulfoaryl substituents reduce potency of 8-phenyltheophylline, yielding water-soluble adenosine antagonists, which are some 2-5-fold more potent than theophylline at adenosine receptors. None of the 8-(substituted phenyl)theophyllines are particularly selective as antagonists toward A1- and A2-adenosine receptors. 1,3-Dipropyl-8-phenylxanthine represents a potent and somewhat selective A1-receptor antagonist about 23-fold more potent at A1 receptors than at A2 receptors. A p-hydroxyaryl substituent further enhances potency of the 1,3-dipropyl-8-phenylxanthine at both A1 and A2 receptors. The 8-(2-amino-4-chlorophenyl)-1,3-dipropylxanthine is a very potent and selective antagonist for A1 receptors, being nearly 400-fold more potent at A1 than at A2 receptors. The water-soluble 8-(p-sulfophenyl)- and 8-(p-carboxyphenyl)-1,3-propylxanthines no longer exhibit marked selectivity. Both compounds are much more potent as adenosine antagonists than theophylline. The striking selectivity of 1-isoamyl-3-isobutylxanthine as an A1 antagonist is retained in the 8-phenyl derivative but is virtually lost in the 8-p-sulfophenyl derivative.
authors.forename: J W
authors.initials: JW
authors.lastname: Daly
authors.forename: W
authors.initials: W
authors.lastname: Padgett
authors.forename: M T
authors.initials: MT
authors.lastname: Shamim
authors.forename: P
authors.initials: P
authors.lastname: Butts-Lamb
authors.forename: J
authors.initials: J
authors.lastname: Waters
mesh_terms: D000241:Adenosine / Q000037:antagonists & inhibitors*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D066298:In Vitro Techniques; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011983:Receptors, Purinergic; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D011956:Receptors, Cell Surface; D011983:Receptors, Purinergic; D000241:Adenosine