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 [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-α (TNF-α) production and leukopenia in mice. KF24345 (10 mg/kg p.o.) significantly suppressed the elevation of serum TNF-α 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-α 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.
Abbreviations
- KF24345
- 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride
- LPS
- lipopolysaccharide
- TNF-α
- tumor necrosis factor-α
- ZM 241385
- 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol
- 8-SPT
- 8-(p-sulfophenyl)theophylline
- R75231
- 2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide
- KW-3902
- 8-(noradamantan-3-yl)-1,3-dipropylxanthine
- Received May 30, 2001.
- Accepted September 21, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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