120362-55-2Relevant academic research and scientific papers
2-Phenylimidazo[2,1-i]purin-5-ones: Structure-activity relationships and characterization of potent and selective inverse agonists at human A3 adenosine receptors
Ozola, Vita,Thorand, Mark,Diekmann, Martina,Qurishi, Ramatullah,Schumacher, Britta,Jacobson, Kenneth A.,Mueller, Christa E.
, p. 347 - 356 (2007/10/03)
Structure-activity relationships of 2-phenyl-imidazo[2,1-i]purin-5-ones as ligands for human A3 adenosine receptors (ARs) were investigated. An ethyl group in the 8-position of the imidazoline ring of 4-methyl-2-phenyl-imidazopurinone leading to chiral compounds was found to increase affinity for human A3 ARs by several thousand-fold. Propyl substitution instead of methyl at N4 decreased A3 affinity but increased A1 affinity leading to potent A1-selective AR antagonists. The most potent A1 antagonist of the present series was (S)-8-ethyl-2-phenyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one (S-3) exhibiting a Ki value of 7.4 nM at rat A1 ARs and greater than 100-fold selectivity versus rat A2A and human A3 ARs. At human A1 ARs 2-phenylimidazo[2,1-i]purin-5-ones were generally less potent and therefore less A1-selective (S-3: Ki=98 nM). 2-, 3-, or 4-Mono-chlorination of the 2-phenyl ring reduced A3 affinity but led to an increase in affinity for A1 ARs, whereas di- (3,4-dichloro) or polychlorination (2,3,5-trichloro) increased A3 affinity. The most potent and selective A3 antagonist of the present series was the trichlorophenyl derivative (R)-8-ethyl-4-methyl-2-(2,3,5-trichlorophenyl)-4,5,7,8-tetrahydro-1H- imidazo[2,1-i]purin-5-one (R-8) exhibiting a subnanomolar Ki value at human A3 ARs and greater than 800-fold selectivity versus the other AR subtypes. Methylation of 4-alkyl-2-phenyl-substituted imidazo[2,1-i]purin-5-ones led exclusively to the N9-methyl derivatives, which exhibited largely reduced AR affinities as compared to the unmethylated compounds. [35S]GTPγS binding studies of the most potent 2-phenyl-imidazo[2,1-i]purin-5-ones at membranes of Chinese hamster ovary cells expressing the human A3 AR revealed that the compounds were inverse agonists at A3 receptors under standard test conditions. Due to their high A3 affinity, selectivity, and relatively high water-solubility, 2-phenyl-imidazo[2,1-i]purin-5-ones may become useful research tools.
Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions
Shamim,Ukena,Padgett,Daly
, p. 1231 - 1237 (2007/10/02)
The effects of 8-phenyl and 8-cycloalkyl substituents on the activity of theophylline, caffeine, 1,3-dipropylxanthine, 1,3-dipropyl-7-methylxanthine, 3-propylxanthine, and 1-propylxanthine at A1 adenosine receptors of rat brain and fat cels and at A2 adenosine receptors of rat pheochromocytoma PC12 cells and human platelets are compared. An 8-phenyl substituent has little effect on the activity of caffeine or 1,3-dipropyl-7-methylxanthine at adenosine receptors, while markedly increasing activity of theophylline, 1,3-dipropylxanthine, 1-isoamyl-3-isobutylxanthine, 1-methylxanthine, and 3-propylxanthine. 8-Phenyl-1-propylxanthine is potent (K(i) = 20-70 nM) at all receptors. A p-carboxy or p-sulfo substituent, which is introduced on the 8-phenyl ring to increase water solubility, in most cases decreases the activity and selectivity for the A1 receptor. Among the 8-p-sulfo analogues, only 8-(p-sulfophenyl)theophylline and 1,3-dipropyl-8-(p-sulfophenyl)xanthine are selective for the A1 receptors. 8-p-Sulfophenyl derivatives of caffeine, 1,3-dipropyl-7-methylxanthine, and 3-propylxanthine are somewhat selective for the A2 receptors. 8-Cycloalkyl substituents (cyclopentyl, cyclohexyl) markedly increase activity of caffeine and 1,3-dipropyl-7-methylxanthine at the A2 receptor. 8-Cyclohexylcaffeine is potent (K(i) = 190 nM) and very selective for the human platelet A2 receptors, but is not as selective for the rat PC12 cell A2 receptor. Such A2 selectivity is in contrast to the marked A1 selectivity of 8-cycloalkyltheophyllines and 8-cycloalkyl-1,3-dipropylxanthines. The apparent selectivity of certain xanthines is dependent on the assay systems that are compared.
