Pharmacological characterization of a novel long-acting histamine H1 receptor antagonist, KAA-276.

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.

• 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)

Chemical References

• Azocines
• Benzimidazoles
• Histamine H1 Antagonists
• KAA 276
• Receptors, Histamine H1
• Ketotifen

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)