150821-03-7

In the radioligand binding assay, Pranlukast (ONO-1078) inhibits [ ³ H]LTE ₄ , [ ³ H]LTD ₄ , and [ ³ H]LTC ₄ bindings to lung membranes with K _i s of 0.63±0.11, 0.99±0.19, and 5640±680 nM, respectively. The antagonism of Pranlukast against [ ³ H]LTD ₄ binding is competitive. In functional experiments, Pranlukast shows competitive antagonism against the LTC ₄ - and LTD ₄ -induced contractions of guinea pig trachea and lung parenchymal strips with a pA ₂ range of 7.70 to 10.71. In the presence of an inhibitor of the bioconversion of LTC ₄ to LTD ₄ , Pranlukast also antagonizes the LTC ₄ -induced contraction of guinea pig trachea (pA ₂ =7.78). Pranlukast significantly reverses the LTD ₄ -induced prolonged contraction without effect on the KCl- and BaCl ₂ -induced contractions of guinea pig trachea. Oxygen-glucose deprivation (OGD)-induced nuclear translocation of CysLT ₁ receptors is inhibited by pretreatment with the CysLT ₁ receptor antagonist Pranlukast (10 μM). Pranlukast protects endothelial cells against ischemia-like injury. The effects of the CysLT ₁ receptor antagonist Pranlukast and the 5-lipoxygenase inhibitor Zileuton on translocation are also assessed. The results show that Pranlukast, but not Zileuton, inhibits the translocation of the CysLT ₁ receptor 6 h after OGD.

Carrageenan (CAR, 5 mg per mouse) is injected i.p. 24 h before LPS (50 p,g per mouse) is injected i.v. Various doses of Pranlukast (ONO-1078; 40, 20, and 10 mmol/kg), AA-861 (20, 10, and 5 mmol/kg), Indomethacin (40 mmollkg), and the controls are injected s.c. into mice 30 min before they are challenged with 50 p,g of LPS. The maximum soluble doses are 0.6 mmol/mL in 10% DMSO for AA-861 and 1.2 mmol/mL in 10% ethanol for Pranlukast. These solutions are used as the maximum doses for the treatments. The mortality of mice is significantly decreased in AA-861- Pranlukast-treated mice relative to that in the control mice. Pretreatment with CAR (5 mg i.p.) renders the mice more sensitive to the effect of LPS. Although the survival rate of mice treated with each solvent is 20% at 72 h after LPS (50 p,g per mouse) administration, s.c. treatment with AA-861 (20 mmol/kg) or Pranlukast (40 mmol/kg) significantly increases the survival rate after the LPS administration (AA-861, P<0.001; Pranlukast, P<0.01).