KF24345, an adenosine uptake inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia via endogenous adenosine in mice.
3-[1-(6,7-Diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345) is a novel potent adenosine uptake inhibitor. KF24345 inhibited [(3)H]adenosine uptake into erythrocytes from human, mouse, rabbit, and hamster with IC(50) values of 59.5, 130.1, 104.2, and 30.9 nM, respectively. In mice, oral administration of KF24345 at 10 mg/kg almost completely inhibited the [(3)H]adenosine uptake into sampled blood cells at least up to 10 h of the administration. In this study, to examine whether the adenosine uptake inhibition exhibits anti-inflammatory effects, we determined the effects of KF24345 on lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) production and leukopenia in mice. KF24345 (10 mg/kg p.o.) significantly suppressed the elevation of serum TNF-alpha concentration after the LPS injection, and the suppressing effect of KF24345 was abolished by the treatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol, a selective adenosine A(2) receptor antagonist, but not with 8-(noradamantan-3-yl)-1,3-dipropylxanthine, a selective adenosine A(1) receptor antagonist. KF24345 (10 mg/kg p.o.) also inhibited the decrease of leukocytes after the LPS injection, and 8-(p-sulfophenyl)theophylline, a nonselective adenosine receptor antagonist, completely reversed the inhibitory effect of KF24345. These results demonstrate that KF24345 inhibits LPS-induced TNF-alpha production and leukopenia via enhancing the effect of endogenous adenosine. It is thus suggested that the adenosine uptake inhibitor has anti-inflammatory effects in vivo and represents a novel therapeutic approach to the treatment of various inflammatory diseases.
Noji
Tohru
T
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan. tohru.noji@kyowa.co.jp
Takayama
Makoto
M
Mizutani
Mirai
M
Okamura
Yuko
Y
Takai
Haruki
H
Karasawa
Akira
A
Kusaka
Hideaki
H
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D006224:Cricetinae; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008647:Mesocricetus; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011817:Rabbits; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C444645:3-(1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl)-1,6-dimethyl-2,4-(1H,3H)-quinazolinedione; D008070:Lipopolysaccharides; D014179:Neurotransmitter Uptake Inhibitors; D011744:Pyrimidinones; D011799:Quinazolines; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D000241:Adenosine