Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure-activity relationships at adenosine receptors

J Med Chem. 1993 Oct 29;36(22):3341-9. doi: 10.1021/jm00074a015.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / ultrastructure
  • Radioligand Assay
  • Rats
  • Receptors, Purinergic P1 / drug effects*
  • Receptors, Purinergic P1 / metabolism
  • Structure-Activity Relationship
  • Theophylline / analogs & derivatives
  • Theophylline / chemical synthesis*
  • Theophylline / metabolism
  • Theophylline / pharmacology*
  • Xanthines / chemical synthesis*
  • Xanthines / metabolism
  • Xanthines / pharmacology*

Substances

  • Receptors, Purinergic P1
  • Xanthines
  • Theophylline
  • 1,7-dimethylxanthine