Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors.

Abstract

Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [( 3H]-N6-(phenylisopropyl)adenosine as radioligand] or striatum [3H]-5'-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxy-methyl)oxyl] phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was greater than 740-fold A1 selective.

Cite this paper

@article{Jacobson1989Sulfurcontaining1D, title={Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors.}, author={Kenneth A. Jacobson and L Kiriasis and Sharone Barone and Barton J Bradbury and Udai S. Kammula and Jean Marc Campagne and S I Secunda and John William Daly and John L. Neumeyer and W. Pfleiderer}, journal={Journal of medicinal chemistry}, year={1989}, volume={32 8}, pages={1873-9} }