| Abstract
| - 4-(Phenylethynyl)-6-phenyl-1,4-dihydropyridinederivatives are selective antagonists at humanA3 adenosine receptors, with Kivalues in a radioligand binding assay vs[125I]AB-MECA(N6-(4-amino-3-iodobenzyl)-5‘-(N-methylcarbamoyl)adenosine)in the submicromolar range. In thisstudy, structure−activity relationships at various positions of thedihydropyridine ring (the 3-and 5-acyl substituents, the 4-aryl substituent, and 1-methyl group)were probed synthetically.Using the combined protection of the 1-ethoxymethyl and the5-[2-(trimethylsilyl)ethyl] estergroups, a free carboxylic acid was formed at the 5-position allowingvarious substitutions.Selectivity of the new analogues for cloned human A3adenosine receptors was determined vsradioligand binding at rat brain A1 and A2Areceptors. Structure−activity analysis at adenosinereceptors indicated that pyridyl, furyl, benzofuryl, and thienyl groupsat the 4-position resultedin, at most, only moderate selectivity for A3 adenosinereceptors. Ring substitution (e.g.,4-nitro)of the 4-phenylethynyl group did not provide enhanced selectivity, asit did for the 4-styryl-substituted dihydropyridines. At the 3-position of thedihydropyridine ring, esters were muchmore selective for A3 receptors than closely relatedthioester, amide, and ketone derivatives.A cyclic 3-keto derivative was 5-fold more potent atA3 receptors than a related open-ringanalogue. At the 5-position, a homologous series of phenylalkylesters and a series of substitutedbenzyl esters were prepared and tested. (Trifluoromethyl)-,nitro-, and other benzyl esterssubstituted with electron-withdrawing groups were specific forA3 receptors with nanomolarKi values and selectivity as high as 37000-fold.A functionalized congener bearing an[(aminoethyl)amino]carbonyl group was also prepared as anintermediate in the synthesis ofbiologically active conjugates.
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