8-substituted xanthines as antagonists at A1- and A2-adenosine receptors

Kenneth A. Jacobson, Richard De La Cruz, Richard Schulick, Leonidas Kiriasis, William Padgett, Wolfgang Pfleiderer, Kenneth L. Kirk, John L. Neumeyer, John W. Daly

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Two classes of 8-substituted analogs of theophylline (1,3-dialkylxanthines), having 8-cycloalkyl, 8-cycloalkenyl or 8-(para-substituted aryl) groups, were shown to be potent and, in some cases, receptor subtype selective antagonists at A1- and A2-adenosine receptors. New analogs based on a functionalized cogener approach and on classical medicinal chemical approaches were prepared. Affinity at A1-adenosine receptors was evaluated by inhibition of binding of [3H]N6-phenylisopropyladenosine to rat brain membranes. Activity at A2-adenosine receptors was measured by the reversal of 5'-N-ethylcarboxamidoadenosine (NECA)-stimulated production of cyclic AMP in membranes from rat pheochromocytoma PC12 cells. Cycloalkenyl analogs containing rigid olefinic bonds differed greatly in potency from the saturated analogs. The selectivity of phenylsulfonamide analogs depended on distal structural features. Novel xanthine analogs include diamino-, thiol-, aldehyde, and halogen-substituted derivatives, peptide conjugates of 8-[4-[2-aminoethylaminocarbonylmethyloxy]phenyl]1,3-dipropylxanthine (XAC), and a hydroxyethylamide analog of XAC.

Original languageEnglish (US)
Pages (from-to)3653-3661
Number of pages9
JournalBiochemical Pharmacology
Issue number19
StatePublished - Oct 1 1988
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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