Effects of ONO-6950, a novel dual cysteinyl leukotriene 1 and 2 receptors antagonist, in a guinea pig model of asthma
| Autor: | Fumio Nambu, Manabu Fujita, Takafumi Nakao, Hiroaki Nomura, Shinji Nakade, Kazuhito Kawabata, Yasuo Yonetomi, Tetsuya Kitamine, Atsuto Inoue, Shintaro Nakao, Masayuki Murata, Tomohiko Sekioka, Michiaki Kadode, Akihiro Kamiya |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
Indoles medicine.drug_class Guinea Pigs Respiratory System Administration Oral CHO Cells Pharmacology Capillary Permeability Guinea pig chemistry.chemical_compound Cricetulus medicine Animals Receptor Montelukast Receptors Leukotriene Dose-Response Relationship Drug Molecular Structure biology Chemistry Antagonist Glutathione Receptor antagonist Asthma Butyrates Disease Models Animal Ovalbumin biology.protein Leukotriene Antagonists Calcium Bronchoconstriction medicine.symptom medicine.drug |
| Zdroj: | European Journal of Pharmacology. 765:242-248 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2015.08.041 |
| Popis: | We assessed in this study the anti-asthmatic effects of ONO-6950, a novel cysteinyl leukotriene 1 (CysLT1) and 2 (CysLT2) receptors dual antagonist, in normal and S-hexyl glutathione (S-hexyl GSH)-treated guinea pigs, and compared these effects to those of montelukast, a CysLT1 selective receptor antagonist. Treatment with S-hexyl GSH reduced animals LTC4 metabolism, allowing practical evaluation of CysLT2 receptor-mediated airway response. ONO-6950 antagonized intracellular calcium signaling via human and guinea pig CysLT1 and CysLT2 receptors with IC50 values of 1.7 and 25 nM, respectively (human receptors) and 6.3 and 8.2 nM, respectively (guinea pig receptors). In normal guinea pigs, both ONO-6950 (1 or 0.3 mg/kg, p.o.) and the CysLT1 receptor antagonist montelukast (0.3 or 0.1 mg/kg, p.o.) fully attenuated CysLT1-mediated bronchoconstriction and airway vascular hyperpermeability induced by LTD4. On the other hand, in S-hexyl GSH-treated guinea pigs ONO-6950 at 3 mg/kg, p.o. or more almost completely inhibited bronchoconstriction and airway vascular hyperpermeability elicited by LTC4, while montelukast showed only partial or negligible inhibition of these airway responses. In ovalbumin sensitized guinea pigs, treatment with S-hexyl GSH on top of pyrilamine and indomethacin rendered antigen-induced bronchoconstriction sensitive to both CysLT1 and CysLT2 receptor antagonists. ONO-6950 strongly inhibited this asthmatic response to the level attained by combination therapy with montelukast and BayCysLT2RA, a selective CysLT2 receptor antagonist. These results clearly demonstrate that ONO-6950 is an orally active dual CysLT1/LT2 receptor antagonist that may provide a novel therapeutic option for patients with asthma. |
| Databáze: | OpenAIRE |
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