Characterization of the antibronchoconstrictor activity of MEN 11420, a tachykinin NK2 receptor antagonist, in guinea-pigs.
We have investigated the antibronchoconstrictor activity of a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist, MEN 11420 c¿[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2beta-5beta++ +)¿, as compared to MEN 10627 c[(Met-Asp-Trp-Phe-Dpr-Leu)c(2beta-5beta)] and to the nonpeptide antagonist SR 48968 ((S)-N-methyl-N[4-acetylamino-4-phenylpiperidino-2-3,4-dichlorophenyl)bu tyl] benzamide. In the guinea-pig isolated bronchus MEN 11420 (pK(B) 8.40+/-0.07) and MEN 10627 (pK(B) 8.67+/-0.09) competitively antagonized the contraction induced by the tachykinin NK2 receptor agonist, [betaAla8]neurokinin A-(4-10). SR 48968 showed an apparent pK(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 [betaAla8]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 micromol/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 NK2 receptor in guinea-pig airways with a long duration of action.
Pharmacology Department-Menarini Ricerche, Florence, Italy.
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Patacchini
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Giuliani
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D000595:Amino Acid Sequence; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000097:blood / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*
D001549:Benzamides; D001993:Bronchodilator Agents; C107754:MEN 11420; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C064218:neurokinin A (4-10), beta-Ala(8)-; C090951:MEN 10627; C073839:SR 48968; D001285:Atropine; D015288:Neurokinin A; D002211:Capsaicin