title: 1,8-disubstituted xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists.
abstract: 3-Unsubstituted xanthine derivatives bearing a cyclopentyl or a phenyl residue in the 8-position were synthesized and developed as A2B adenosine receptor antagonists. Compounds bearing polar substituents were prepared to obtain water-soluble derivatives. 1-Alkyl-8-phenylxanthine derivatives were found to exhibit high affinity for A2B adenosine receptors (ARs). 1,8-disubstituted xanthine derivatives were equipotent to or more potent than 1,3,8-trisubstituted xanthines at A2B ARs, but generally less potent at A1 and A2A, and much less potent at A3 ARs. Thus, the new compounds exhibited increased A2B selectivity versus all other AR subtypes. 9-Deazaxanthines (pyrrolo[2,3-d]pyrimidindiones) appeared to be less potent at A2B ARs than the corresponding xanthine derivatives. 1-Propyl-8-p-sulfophenylxanthine (17) was the most selective compound of the present series, exhibiting a K(i) value of 53 nM at human A2B ARs and showing greater than 180-fold selectivity versus human A1 ARs. Compound 17 was also highly selective versus rat A1 ARs (41-fold) and versus the other human AR subtypes (A2A > 400-fold and A3 > 180-fold). The compound is highly water-soluble due to its sulfonate function. 1-Butyl-8-p-carboxyphenylxanthine (10), another polar analogue bearing a carboxylate function, exhibited a K(i) value of 24 nM for A2B ARs, 49-fold selectivity versus human and 20-fold selectivity versus rat A1 ARs, and greater than 150-fold selectivity versus human A2A and A3 ARs. 8-[4-(2-Hydroxyethylamino)-2-oxoethoxy)phenyl]-1-propylxanthine (29) and 1-butyl-8-[4-(4-benzyl)piperazino-2-oxoethoxy)phenyl]xanthine (35) were among the most potent A2B antagonists showing K(i) values at A2B ARs of 1 nM, 57-fold (29) and 94-fold (35) selectivity versus human A1, ca. 30-fold selectivity versus rat A1, and greater than 400-fold selectivity versus human A2A and A3 ARs. The new potent, selective, water-soluble A2B antagonists may be useful research tools for investigating A2B receptor function.
authors.affiliation: University of Bonn, Pharmaceutical Institute Poppelsdorf, Bonn, Germany.
authors.forename: Alaa M
authors.initials: AM
authors.lastname: Hayallah
authors.forename: Jesús
authors.initials: J
authors.lastname: Sandoval-Ramírez
authors.forename: Ulrike
authors.initials: U
authors.lastname: Reith
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schobert
authors.forename: Birgit
authors.initials: B
authors.lastname: Preiss
authors.forename: Britta
authors.initials: B
authors.lastname: Schumacher
authors.forename: John W
authors.initials: JW
authors.lastname: Daly
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D019817:Benzoic Acid / Q000737:chemistry; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D011485:Protein Binding; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014162:Transfection; D014970:Xanthines / Q000737:chemistry*
chemical_list: D000588:Amines; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014970:Xanthines; D019817:Benzoic Acid