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. 2003 Feb 6;11(3):347-56.
doi: 10.1016/s0968-0896(02)00456-x.

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

Vita Ozola  1 , Mark Thorand, Martina Diekmann, Ramatullah Qurishi, Britta Schumacher, Kenneth A Jacobson, Christa E Müller
Affiliations

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

Vita Ozola et al. Bioorg Med Chem. .

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.

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Figures

Figure 1.
Figure 1.
Tautomeric structures and alkylation of imidazo[2,1-i]purin-5-ones.
Figure 2.
Figure 2.
Typical electropherograms of chiral separation of two chiral compounds. A. Racemate RS-8. Inlet buffer: phosphate 50 mM, β-cyclodextrin 6 mM, pH 4.5. Outlet buffer: phosphate 50 mM, sulfated β-cyclodextrin 2.5 mg/mL, pH 4.5. Fused silica capillary, 40 cm effective length×75 μm I.D. ×375 O.D.; constant current: 90 μA; injection time: 5 s with 0.5 p.s.i.; B. Enantiomer S-3. Inlet buffer: phosphate 50 mM, hydroxypropyl-β-cyclodextrin 6 mM, sulfated β-cyclodextrin 1 mg/mL, pH 4.5. Outlet buffer: phosphate 50 mM, sulfated β-cyclodextrin 1 mg/mL, pH 4.5. Fused silica capillary, 50 cm effective length×75 μm I.D.×375 O.D.; constant current: 90 μA; injection time: 20 s with 0.5 p.s.i.
Figure 3.
Figure 3.
pH-Dependence of A1 adenosine receptor affinity of imidazopurinone derivative S-3; Ki values at pH 7.4 and 8.0 were not statistically significantly different from each other; both Ki values were statistically significantly different from Ki value at pH 6.0 (unpaired t-test).
Figure 4.
Figure 4.
Stimulation (by NECA) and inhibition (by 2-phenylimidazo[2,1-i]purin-5-one derivatives R-1 and R-8) of [35S]GTPγS binding to membranes prepared from Chinese hamster ovary cells expressing the human A3 adenosine receptor; NECA (agonist): EC50 = 77 ± 10 nM, max. stimulation (control=100%): 147%; compound R-1: IC50 = 36 ± 3 nM, max. inhibition: to 81%; compound R-8: IC50 = 4.0 ± 0.3 nM, max. inhibition: to 84% of control [35S]GTPγS binding. MRS 1523 caused no significant inhibition of [35S]GTPγS binding.
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