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

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...

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Veröffentlicht in:Journal of medicinal chemistry 1989-08, Vol.32 (8), p.1873-1879
Hauptverfasser: Jacobson, Kenneth A, Kiriasis, Leonidas, Barone, Suzanne, Bradbury, Barton J, Kammula, Udai, Campagne, Jean Michel, Daly, John W, Neumeyer, John L, Pfleiderer, Wolfgang, Secunda, Sherrie
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container_end_page 1879
container_issue 8
container_start_page 1873
container_title Journal of medicinal chemistry
container_volume 32
creator Jacobson, Kenneth A
Kiriasis, Leonidas
Barone, Suzanne
Bradbury, Barton J
Kammula, Udai
Campagne, Jean Michel
Daly, John W
Neumeyer, John L
Pfleiderer, Wolfgang
Secunda, Sherrie
description 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.
doi_str_mv 10.1021/jm00128a031
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subjects Animals
Binding, Competitive
Chemical Phenomena
Chemistry
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives
In Vitro Techniques
Organic chemistry
Preparations and properties
Radioligand Assay
Rats
Receptors, Purinergic - drug effects
Receptors, Purinergic - metabolism
Structure-Activity Relationship
Sulfur
Xanthines - chemical synthesis
Xanthines - metabolism
Xanthines - pharmacology
title Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors
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