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 Paige Hicks, Diane G. Costello, Mary E. Abreu

Research output: Contribution to journalArticle

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Abstract

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
Volume34
Issue number4
DOIs
StatePublished - Apr 1 1991

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Xanthines
Adenosine A2 Receptors
Adenosine A1 Receptors
varespladib methyl

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Erickson, R. H., Hiner, R. N., Feeney, S. W., Blake, P. R., Rzeszotarski, W. J., Hicks, R. P., ... Abreu, M. E. (1991). 1,3,8-Trisubstituted Xanthines. Effects of Substitution Pattern upon Adenosine Receptor A1/A2 Affinity. Journal of Medicinal Chemistry, 34(4), 1431-1435. https://doi.org/10.1021/jm00108a029

1,3,8-Trisubstituted Xanthines. Effects of Substitution Pattern upon Adenosine Receptor A1/A2 Affinity. / Erickson, Ronald H.; Hiner, Roger N.; Feeney, Scott W.; Blake, Paul R.; Rzeszotarski, Waclaw J.; Hicks, Rickey Paige; Costello, Diane G.; Abreu, Mary E.

In: Journal of Medicinal Chemistry, Vol. 34, No. 4, 01.04.1991, p. 1431-1435.

Research output: Contribution to journalArticle

Erickson, RH, Hiner, RN, Feeney, SW, Blake, PR, Rzeszotarski, WJ, Hicks, RP, Costello, DG & Abreu, ME 1991, '1,3,8-Trisubstituted Xanthines. Effects of Substitution Pattern upon Adenosine Receptor A1/A2 Affinity', Journal of Medicinal Chemistry, vol. 34, no. 4, pp. 1431-1435. https://doi.org/10.1021/jm00108a029
Erickson, Ronald H. ; Hiner, Roger N. ; Feeney, Scott W. ; Blake, Paul R. ; Rzeszotarski, Waclaw J. ; Hicks, Rickey Paige ; Costello, Diane G. ; Abreu, Mary E. / 1,3,8-Trisubstituted Xanthines. Effects of Substitution Pattern upon Adenosine Receptor A1/A2 Affinity. In: Journal of Medicinal Chemistry. 1991 ; Vol. 34, No. 4. pp. 1431-1435.
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