KF24345, an adenosine uptake inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia via endogenous adenosine in mice.

Abstract

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.

• Authors: Tohru Noji, Makoto Takayama, Mirai Mizutani, Yuko Okamura, Haruki Takai, Akira Karasawa, Hideaki Kusaka
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 300 Issue 1 Pg. 200-5 (Jan 2002) ISSN: 0022-3565 [Print] United States
• PMID: 11752117 (Publication Type: Journal Article)

Chemical References

• 3-(1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl)-1,6-dimethyl-2,4-(1H,3H)-quinazolinedione
• Lipopolysaccharides
• Neurotransmitter Uptake Inhibitors
• Pyrimidinones
• Quinazolines
• Receptors, Purinergic P1
• Tumor Necrosis Factor-alpha
• Adenosine

Topics

• Adenosine (metabolism)
• Animals
• Cricetinae
• Erythrocytes (drug effects, metabolism)
• Humans
• Leukopenia (chemically induced)
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Mesocricetus
• Mice
• Neurotransmitter Uptake Inhibitors (pharmacology)
• Pyrimidinones (pharmacology)
• Quinazolines (pharmacology)
• Rabbits
• Receptors, Purinergic P1 (drug effects)
• Tumor Necrosis Factor-alpha (biosynthesis)