title: 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.affiliation: Central Research Laboratory, Kissei Pharmaceutical Co. Ltd., Minamiazumi, Nagano Prefecture, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Takehana
authors.forename: K
authors.initials: K
authors.lastname: Shinagawa
authors.forename: S
authors.initials: S
authors.lastname: Tsuyuki
authors.forename: Y
authors.initials: Y
authors.lastname: Tokutake
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: D
authors.initials: D
authors.lastname: Momose
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001392:Azocines / Q000008:administration & dosage / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007665:Ketotifen / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D001392:Azocines; D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; C112798:KAA 276; D011969:Receptors, Histamine H1; D007665:Ketotifen