Pharmacological Characterization of a Novel Long-acting Histamine H1 Receptor Antagonist, KAA-276
| Autor: | Den-ichi Momose, Masaaki Sato, Toshiro Kobayashi, Yoshiki Tokutake, Shogo Tsuyuki, Kazuhiko Shinagawa, Yasuo Toyoshina Takehana |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Ketotifen medicine.drug_class Bronchoconstriction medicine.medical_treatment Guinea Pigs Mepyramine Administration Oral Pharmaceutical Science Histamine H1 receptor Pharmacology Radioligand Assay chemistry.chemical_compound Administration Inhalation medicine Animals Receptors Histamine H1 Antagonist Muscle Smooth General Medicine Receptor antagonist Azocines Rats chemistry Astemizole Anesthesia Histamine H1 Antagonists Benzimidazoles Antihistamine Histamine Muscle Contraction medicine.drug |
| Zdroj: | Biological and Pharmaceutical Bulletin. 21:350-355 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.21.350 |
| Popis: | The pharmacological profile of a newly synthesized histamine H, receptor antagonist, KAA-276 (1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-carboxyethyl)-phenyl]ethyl]-1,5-diazacyclooctane sulfate), was characterized. In a H, receptor binding assay in vitro, KAA-276 inhibited [ 3 H]mepyramine binding to guinea pig cerebellar membrane preparations with an IC 50 of 0.66 nM. The inhibitory potency of KAA-276 was greater than that of terfenadine, but similar to that of astemizole and ketotifen. KAA-276 antagonized the histamine-induced constriction of ileum and trachea isolated from guinea pigs in a dose-dependent manner with a concomitant reduction in the maximum response. Furthermore, the inhibitory effect of KAA-276 on histamine induced contraction was potentiated depending on the duration of preincubation time and revealed an irreversible property. KAA-276 given orally, intraduodenally, and by inhalation significantly inhibited histamine-induced bronchoconstriction dose-dependently in guinea pigs. Inhalation of KAA-276 exhibited inhibitory activity with a rapid onset and long duration, while intraduodenal administration resulted in action with a slow onset. Therefore, KAA-276, an irreversible and selective histamine H, receptor antagonist, was shown to be a useful drug for therapeutic strategies against bronchial asthma when administered by the aerosol route. |
| Databáze: | OpenAIRE |
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