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 xa nthines, including paraxanthine analogs (1,7-disubstituted xanthines) and 1,8-disubstituted xanthines, were developed. Silylation of 1-subst ituted xanthines followed by alkylation at the 7-position provides a f acile 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 procedu res. The ring closure of 3-substituted 5-cyclopentanecarboxamido- and 5-(benzoylamino)-6-aminouracils requires drastic reaction conditions. Affinity for brain Al and A2 adenosine receptors was determined in bin ding 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-D isubstituted xanthines had high affinity for adenosine receptors; some were highly selective for Al receptors.