8-Aryl- and 8-Cycloalkyl-1,3-dipropylxanthines: Further Potent and Selective Antagonists for A1-Adenosine Receptors

M. T. Shamim, D. Ukena, W. L. Padgett, O. Hong, J. W. Daly

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A series of 1,3-dipropylxanthines were prepared with a variety of substituents at the 8-position. These included 8-aryl and 8-cycloalkyl groups. Polar carboxylate and carboxamide moieties’ were introduced as aryl substituents to increase water solubility. 1,3-Dipropyl-8-[2-hydroxy-4-[(carboxymethyl)oxy]phenyl]xanthine provided a functionalized congener with high potency (Ki= 37 nM) and selectivity (54-fold) for A1-adenosine receptors. This congener was used for preparation of a series of other analogues, some with higher potency and some with higher selectivity. 8-Cyclopentyl- and 8-cyclohexyl-1,3-dipropylxanthines were both very potent (Ki= 1-1.5 nM) and selective for A1receptors, while 8-cycloalkylmethyl analogues were 10-fold less potent, but still very selective for A1receptors. 8-Piperidinyl and 8-pyrazinyl analogues had very low activities as adenosine receptor antagonists.

Original languageEnglish (US)
Pages (from-to)613-617
Number of pages5
JournalJournal of medicinal chemistry
Issue number3
StatePublished - Mar 1 1988

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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