1,3,8-Trisubstituted Xanthines. Effects of Substitution Pattern upon Adenosine Receptor A1/A2 Affinity

Ronald H. Erickson, Roger N. Hiner, Scott W. Feeney, Paul R. Blake, Waclaw J. Rzeszotarski, Rickey P. Hicks, Diane G. Costello, Mary E. Abreu

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48 Scopus citations


A series of 11 8-substituted xanthines having three different substitution patterns on the 1- and 3-positions [pattern a (R1 = R3 = CH2CH2CH3), b (R1 = CH2CH2CH3, R3 = CH3), and c (R1 = CH3, R3 = CH2CH2CH3)] was prepared. These compounds were assessed for affinity and selectivity in binding to adenosine A1 and A2 receptors. Compounds with greatest affinity at the A1 receptor had the 1,3-substitution pattern a. With one exception, compounds with pattern a also exhibited the most potent binding at the A2 receptor; however, several compounds with pattern c were equipotent at the A2 receptor with those having pattern a. Additionally, the substituants on the 1- and 3-positions of these 8-substituted xanthines were equally important for determining maximum affinity to the A1 receptor, while the substituent at the 3-position is more important than the substituent at the 1-position for potency at the A2 receptor. As a result of this, it is possible to maximize selectivity for the A1 receptor by choice of the 1- and 3-position substituents. However, the R1/R3 substitution pattern required for maximum A1 selectivity is also dependent upon the substituent in the 8-position in a manner which is not fully understood.

Original languageEnglish (US)
Pages (from-to)1431-1435
Number of pages5
JournalJournal of Medicinal Chemistry
Issue number4
StatePublished - Apr 1 1991

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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