Structure-activity relationships of 1,3-dialkylxanthine derivatives at rat A3 adenosine receptors.
1,3-Dialkylxanthine analogues containing carboxylic acid and other charged groups on 8-position substituents were synthesized. These derivatives were examined for affinity in radioligand binding assays at rat brain A3 adenosine receptors stably expressed in CHO cells using the new radioligand [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide), and at rat brain A1 and A2a receptors using [3H]PIA and [3H]CGS 21680, respectively. A synthetic strategy for introducing multiple carboxylate groups at the 8-position using iminodiacetic acid derivatives was explored. The presence of a sulfonate, a carboxylate, or multiple carboxylate groups did not result in a significant enhancement of affinity at rat A3 receptors, although as previously observed an anionic group tended to diminish potency at A1 and A2a receptors. The rat A3 receptor affinity was not highly dependent on the distance of a carboxylate group from the xanthine pharmacophore. 2-Thio vs 2-oxo substitution favored A3 potency, and 8-alkyl vs 8-aryl substitution favored A3 selectivity, although few derivatives were truly selective for rat A3 receptors. 1,3-Dimethyl-8-(3-carboxypropyl)-2-thioxanthine was 7-fold selective for A3 vs A2a receptors. 1,3,7-Trimethyl-8-(trans-2-carboxyvinyl)xanthine was somewhat selective for A3 vs A1 receptors. For 8-arylxanthines affinity at A3 receptors was enhanced by 1,3-dialkyl substituents, in the order dibutyl > dipropyl > diallyl.
Kim
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Molecular Recognition Section, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Ji
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Melman
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Olah
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Stiles
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Jacobson
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D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D016466:CHO Cells; D002110:Caffeine / Q000031:analogs & derivatives; D006224:Cricetinae; D015870:Gene Expression; D007457:Iodine Radioisotopes; D015394:Molecular Structure; D010627:Phenethylamines / Q000378:metabolism; D010660:Phenylisopropyladenosine / Q000378:metabolism; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D014970:Xanthines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D007457:Iodine Radioisotopes; D010627:Phenethylamines; D018047:Receptors, Purinergic P1; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D010660:Phenylisopropyladenosine; D002110:Caffeine; C089722:N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide; D000241:Adenosine