+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

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

, : 2-Phenylimidazo[2,1-i]purin-5-ones: structure-activity relationships and characterization of potent and selective inverse agonists at Human A3 adenosine receptors. Bioorganic & Medicinal Chemistry 11(3): 347-356

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.


PMID: 12517430

Other references

Martínez V.J.árez W.G.rcía, 1992: Numerical calculation of radiative corrections to the beta energy spectrum of semileptonic decays of light- and charm-quark charged baryons. Physical Review. D, Particles and Fields 46(1): 322-336

Sato, Yuichi; Matsumoto, Naoya; Takayama, Tadateru; Tani, Shigemasa; Uchiyama, Takahisa; Saito, Satoshi; Kimura, Shunichi; Orime, Yukihiko; Inoue, Fumio; Furuhashi, Satoru; Takahashi, Motoichiro, 2005: MDCT detection of right ventricle-pulmonary artery bypass stenosis in corrected tetralogy of Fallot. Diagnosis of right ventricle (RV)-pulmonary artery (PA) bypass stenosis after correction of tetralogy of Fallot by echocardiography and right ventriculography is often difficult because of the lack of three-dimensional (3D) information. Since mult...

Behr, L., 1961: Investigations on the resistance and susceptibility of various apple varieties to Ph. cactorum (Leb. et Cohn) Schroet. Among 36 varieties, the most resistant were James Grieve and Cox Samling (Muncheberg) . Malus IX was the most resistant of the rootstocks tested.

Devlin, J.G., 1966: Evidence for the existence of an IgM immuno-globulin to insulin. Irish Journal of Medical Science 6(491): 507-510

Humphries, Christopher J., 2000: Form, space and time; which comes first?. Journal of Biogeography 27(1): 15

Academie D.Agriculture D.France, 1964: Meeting of the French Academy of Agriculture, 8 January 1964. Selected cites and abstracts of the 7 papers in French will appear in pertinent sections of BIOLOGICAL

Ogasawara, H.; Inagawa, T.; Yamamoto, M.; Kamiya, K.; Yano, T.; Utsunomiya, H., 1988: Medulloblastoma in infancy associated with omphalocele, malrotation of the intestine, and extrophy of the bladder. A successfully treated case of infantile medulloblastoma is presented that was associated with omphalocele, malrotation of the intestine, and extrophy of the bladder. A 5-month-old boy was admitted due to disturbance of consciousness and was diagn...

Tamura, S.; Kurata, T., 1997: Mucosal immune responses against influenza virus. The respiratory tract-mucosa is the site of either contact with influenza virus or defense against the virus. Such a defense is mediated by immune competent cells. The precursors of IgA-producing B cells and immune T cells are first induced in the...

Malaguarnera, M.; D.F.zio, I.; Romeo, M.A.tonietta; Restuccia, S.; Laurino, A.; Trovato, B.A.riana, 1997: Elevation of interleukin 6 levels in patients with chronic hepatitis due to hepatitis C virus. Interleukin 6 (IL-6) is a pleiotropic cytokine produced by a wide variety of lymphoid and non-lymphoid tissues. We studied the relationship between IL-6 and the liver in an attempt to elucidate this cytokine's role in hepatitis C-induced live...

Snawdon, J.W.E., 2012: The value of X-rays in dentistry. Medical Press 217(12): 218-221