SULFER-CONTAINING XANTHINE DERIVATIVES AS ADENOSIN ANTAGONISTS

摘要

Sulfur-containing analogs of 8-substituted xanthines were prepared in an effort to increase selectively 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 thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl groups as a prosthetic group for selective iodination via its Hg<+2> derivative was explored. Receptor selectively was determined in binding assays using membrane homogenates from rat cortex ([<3>H]N<6>-phenylisopropyl-adenosine as radioligand) or striatum ([<3>H]N-ethylcarboxamido-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 analog. 2-Thio-8-aryl derivatives tended to be more potent at A2-receptors than the oxygen analog. 1,3-Dipropyl-8-(2-thienyl)-2-thioxanthine was >285-fold A1-selective.