2-Phenylimidazo[2,1-i]purin-5-ones Structure–Activity relationships and characterization of potent and selective inverse agonists at Human A3 adenosine receptors

Abstract

Structure-activity relationships of 2-phenyl-imidazo[2,1-i]purin-5-ones as ligands for human A(3) 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 A(3) ARs by several thousand-fold. Propyl substitution instead of methyl at N4 decreased A(3) affinity but increased A(1) affinity leading to potent A(1)-selective AR antagonists. The most potent A(1) 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 K(i) value of 7.4 nM at rat A(1) ARs and greater than 100-fold selectivity versus rat A(2A) and human A(3) ARs. At human A(1) ARs 2-phenylimidazo[2,1-i]purin-5-ones were generally less potent and therefore less A(1)-selective (S-3: K(i)=98 nM). 2-, 3-, or 4-Mono-chlorination of the 2-phenyl ring reduced A(3) affinity but led to an increase in affinity for A(1) ARs, whereas di- (3,4-dichloro) or polychlorination (2,3,5-trichloro) increased A(3) affinity. The most potent and selective A(3) 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 K(i) value at human A(3) 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]GTP gamma S 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 A(3) AR revealed that the compounds were inverse agonists at A(3) receptors under standard test conditions. Due to their high A(3) affinity, selectivity, and relatively high water-solubility, 2-phenyl-imidazo[2,1-i]purin-5-ones may become useful research tools.

Antinociceptive Effects of Novel A2B Adenosine Receptor Antagonists

“…The A 3 adenosine receptor antagonist PSB-10 significantly increased pain sensation in the hot-plate test. It should be noted that PSB-10 is a very potent and selective A 3 antagonist in humans (Ozola et al, 2003), but it may be less potent at mouse A 3 receptors. Highly potent and selective rodent A 3 antagonists are currently not available (Mü ller, 2003).…”

The A3Adenosine Receptor: History and Perspectives

“…PSB-10 has demonstrated inverse agonist activity in binding studies in CHO cells expressing recombinant hA 3 AR (IC 50 = 4 nM). Another similar compound of this series is 8(R)-ethyl-7,8-dihydro-4-methyl-2-phenyl-1H-imidazo[1,2-g] purin-5-one (PSB-11), exhibiting a K i value of 2.34 nM for the hA 3 AR and good selectivity versus all other AR subtypes (Ozola et al, 2003) (Fig. 2; Table 2).…”

Caffeine analogs: biomedical impact

“…5) has high affinity and selectivity for A 3 -receptors [55]. In addition, so-called extended xanthines, such as PSB-11 [56], the triazolopurine OT-7999 [57] and a pyrrolopurine [58] (see Fig. 5) have high affinity and selectivity for A 3 -receptors.…”