Vol. 300, Issue 1, 200-205, January 2002

KF24345, an Adenosine Uptake Inhibitor, Suppresses Lipopolysaccharide-Induced Tumor Necrosis Factor- Production and Leukopenia via Endogenous Adenosine in Mice

Tohru Noji, Makoto Takayama, Mirai Mizutani, Yuko Okamura, Haruki Takai, Akira Karasawa and Hideaki Kusaka

Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan

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 [³H]adenosine uptake into erythrocytes from human, mouse, rabbit, and hamster with IC₅₀ 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 [³H]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- (TNF-) production and leukopenia in mice. KF24345 (10 mg/kg p.o.) significantly suppressed the elevation of serum TNF- 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 A₂ receptor antagonist, but not with 8-(noradamantan-3-yl)-1,3-dipropylxanthine, a selective adenosine A₁ 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- 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.