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 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.
Laboratory of Chemistry, NIDDK, Bethesda, Maryland 20892.
K A
KA
Jacobson
L
L
Kiriasis
S
S
Barone
B J
BJ
Bradbury
U
U
Kammula
J M
JM
Campagne
S
S
Secunda
J W
JW
Daly
J L
JL
Neumeyer
W
W
Pfleiderer
D000818:Animals; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D011869:Radioligand Assay; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013455:Sulfur; D014970:Xanthines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D011983:Receptors, Purinergic; D014970:Xanthines; D013455:Sulfur