Abstract |
The pharmacological profile of a newly synthesized histamine H1 receptor antagonist, KAA-276 (1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-12-[4-( 2-carboxyethyl)-phenyl]ethyl]-1,5-diazacyclooctane sulfate), was characterized. In a H1 receptor binding assay in vitro, KAA-276 inhibited [3H] mepyramine binding to guinea pig cerebellar membrane preparations with an IC50 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 H1 receptor antagonist, was shown to be a useful drug for therapeutic strategies against bronchial asthma when administered by the aerosol route.
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Authors | T Kobayashi, Y Takehana, K Shinagawa, S Tsuyuki, Y Tokutake, M Sato, D Momose |
Journal | Biological & pharmaceutical bulletin
(Biol Pharm Bull)
Vol. 21
Issue 4
Pg. 350-5
(Apr 1998)
ISSN: 0918-6158 [Print] Japan |
PMID | 9586571
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Azocines
- Benzimidazoles
- Histamine H1 Antagonists
- KAA 276
- Receptors, Histamine H1
- Ketotifen
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Topics |
- Administration, Inhalation
- Administration, Oral
- Animals
- Azocines
(administration & dosage, pharmacology)
- Benzimidazoles
(administration & dosage, pharmacology)
- Bronchoconstriction
(drug effects)
- Guinea Pigs
- Histamine H1 Antagonists
(administration & dosage, pharmacology)
- Ketotifen
(pharmacology)
- Male
- Muscle Contraction
(drug effects)
- Muscle, Smooth
(drug effects)
- Radioligand Assay
- Rats
- Receptors, Histamine H1
(drug effects, metabolism)
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