KF17837 ((E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine), a potent and selective adenosine A2 receptor antagonist.
8-(3,4-Dimethoxystryryl)-1,3-dipropyl-7-methylxanthine exhibited high affinity and selectivity for adenosine A2A receptors in binding assay using rat striatal A2A receptors labeled with [3H]2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosin e (CGS21680). The affinity was stereo selective: the E isomer, KF17837, showed a Ki value of 1.0 +/- 0.057 nM for the A2A receptors, whereas the Z isomer showed much lower affinity. KF17837 had 62-fold selectivity for the A2A receptors versus rat forebrain A1 receptors labeled with [3H]N6-cyclohexyladenosine (CHA). KF17837 was rapidly photoisomerized to form a stable equilibrium mixture (18% E - 82% Z), KF17837S, which showed Ki values of 7.9 +/- 0.055 nM and 390 +/- 68 nM for the A2A and A1 receptors, respectively. The inhibition type was competitive for [3H]CGS21680 binding. In rat pheochromocytoma PC12 cells KF17837S antagonized cAMP accumulation induced by 1 microM CGS21680 via the A2A receptors, with an IC50 value of 53 +/- 10 nM. cAMP accumulation induced by 10 microM 5'-N-ethylcarboxamidoadenosine via the A2B receptors in Jurkat cells (human T-cell line) was inhibited by KF17837S with an IC50 value of 1500 +/- 290 nM. These results indicate that KF17837S (and hence KF17837) is a highly potent and selective adenosine A2A receptor antagonist.
Nonaka
H
H
Pharmaceutical Research Laboratories, Kyowa hakko Kogyo Co., Ltd, Shizuoka, Japan.
Ichimura
M
M
Takeda
M
M
Nonaka
Y
Y
Shimada
J
J
Suzuki
F
F
Yamaguchi
K
K
Kase
H
H
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D008297:Male; D016716:PC12 Cells; D010627:Phenethylamines / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology*
D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D011956:Receptors, Cell Surface; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C081198:KF 17837; D000242:Cyclic AMP; D000241:Adenosine