Characterization of the antibronchoconstrictor activity of MEN 11420, a tachykinin NK 2 receptor antagonist, in guinea-pigs

Abstract

We have investigated the antibronchoconstrictor activity of a novel glycosylated bicyclic peptide tachykinin NK 2 receptor antagonist, MEN 11420 c{[(β- d-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2β–5β)}, as compared to MEN 10627 c[(Met-Asp-Trp-Phe-Dpr-Leu)c(2β–5β)] and to the nonpeptide antagonist SR 48968 (( S)- N-methyl- N[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl)butyl] benzamide. In the guinea-pig isolated bronchus MEN 11420 (p K B 8.40±0.07) and MEN 10627 (p K B 8.67±0.09) competitively antagonized the contraction induced by the tachykinin NK 2 receptor agonist, [βAla 8]neurokinin A-(4–10). SR 48968 showed an apparent p K B of 9.57±0.2. The atropine-resistant response to electrical stimulation was reduced in a concentration-dependent manner by MEN 11420, MEN 10627 and SR 48968. In urethane-anaesthetized guinea-pigs, MEN 11420 produced a dose-dependent inhibition of bronchoconstriction induced by [βAla 8]neurokinin A-(4–10). Comparable inhibitory effects were observed after i.v. administration of SR 48968 and MEN 10627. Bilateral electrical stimulation of the vagi (20 Hz for 20 s) induced a bronchoconstriction that was dose-dependently inhibited by i.v. MEN 11420, SR 48968 and MEN 10627. MEN 11420 was also effective in inhibiting the capsaicin (20 nmol/kg i.v.)-induced bronchoconstriction. MEN 11420 (1.1 μmol/kg i.v.) showed a longer plasma half-life and a greater area under the plasma concentration-time curve value (AUC) than those of MEN 10627. These findings indicate that MEN 11420 is a potent and selective antagonist of the tachykinin NK 2 receptor in guinea-pig airways with a long duration of action.