2-Phenylimidazo[2,1-i]purin-5-ones: structure-activity relationships and characterization of potent and selective inverse agonists at Human A3 adenosine receptors.
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.
Ozola
Vita
V
University of Bonn, Pharmaceutical Institute Poppelsdorf, Kreuzbergweg 26, D-53115 Bonn, Germany.
Thorand
Mark
M
Diekmann
Martina
M
Qurishi
Ramatullah
R
Schumacher
Britta
B
Jacobson
Kenneth A
KA
Müller
Christa E
CE
D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D011688:Purinones / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001555:Benzene Derivatives; D006843:Hydrocarbons, Chlorinated; D007093:Imidazoles; D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D011688:Purinones; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1