453591-08-7Relevant 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.
Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: Potent A2A- and A3-adenosine receptor antagonistst
Müller, Christa E.,Thorand, Mark,Qurishi, Ramatullah,Diekmann, Martina,Jacobson, Kenneth A.,Padgett, William L.,Daly, John W.
, p. 3440 - 3450 (2007/10/03)
A series of tricyclic imidazo[2,1-i]purinones and ring-enlarged analogues derived from xanthine derivatives have been prepared as adenosine receptor (AR) antagonists. In comparison with xanthines, the tricyclic compounds exhibit increased water solubility due to a basic nitrogen atom, which can be protonated under physiological conditions. Substituents were introduced that confer high affinity for A2A or A3 ARs, respectively. A new capillary electrophoresis method was developed for the determination of the enantiomeric purity of selected chiral products using native and modified β-cyclodextrins as chiral discriminators. The compounds were investigated in radioligand binding assays at rat brain A1 and A2A ARs. Selected compounds were additionally investigated in radioligand binding assays at human recombinant A3 ARS and in functional studies (adenylate cyclase assays) at A1 ARs of rat fat cell membranes, A2A ARs of rat PC 12 cell membranes, and mouse A2B ARs of NIH 3T3 cell membranes. Structure-activity relationships were similar to those of corresponding xanthine derivatives. The 2-styrylimidazopurinones were less potent at A2A ARs as compared to 8-styrylxanthine derivatives. The most potent compound at A2A ARs was (S)-1,4-dimethyl-8-ethyl-2-styryl- imidazo[2,1-i]purinone (S-25) exhibiting a Ki value of 424 nM at rat A2A ARs. The compound was highly selective for A2A receptors vs A1 and A3 ARs. Selectivity vs A2B ARs, however, was low. Among the 1-unsubstituted 2-phenyl-imidazo[2,1-i]purin-5-one derivatives, very potent and highly selective antagonists for human A3 ARs were identified. The most potent A3 antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a Ki value of 2.3 nM and high selectivity for A3 receptors vs all other AR subtypes.
