Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure-activity relationships at adenosine receptors.
Synthetic procedures for the preparation of various 3-unsubstituted xanthines, including paraxanthine analogs (1,7-disubstituted xanthines) and 1,8-disubstituted xanthines, were developed. Silylation of 1-substituted xanthines followed by alkylation at the 7-position provides a facile route to paraxanthine analogs. Regioselective alkylation of tris(trimethylsilyl)-6-aminouracil provides 3-substituted 6-aminouracils, which are converted to 1,8-disubstituted xanthines by standard procedures. The ring closure of 3-substituted 5-cyclopentanecarboxamido- and 5-(benzoylamino)-6-aminouracils requires drastic reaction conditions. Affinity for brain A1 and A2 adenosine receptors was determined in binding assays for these and other xanthines with substituents in 1-, 3-, 7-, 8-, and 9-positions. Substitution at the 1-position was necessary for high affinity at adenosine receptors. 1,3-Disubstituted xanthines generally had higher affinity than 1,7-disubstituted xanthines. 1,8-Disubstituted xanthines had high affinity for adenosine receptors; some were highly selective for A1 receptors.
Müller
C E
CE
Pharmazeutisches Institut, Pharmazeutische Chemie, Tübingen, FRG.
Shi
D
D
Manning
M
M
Daly
J W
JW
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014970:Xanthines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
D018047:Receptors, Purinergic P1; D014970:Xanthines; D013806:Theophylline; C021183:1,7-dimethylxanthine