The effect of the tachykinin NK2 receptor antagonist MEN11420 (nepadutant) on neurokinin A-induced bronchoconstriction in asthmatics

Abstract

Objective: We previously reported that the nonpeptide tachykinin NK₂ receptor antagonist SR48968 (saredutant) significantly inhibits neurokinin A-induced bronchoconstriction in patients with asthma. MEN11420 (nepadutant) is a bicyclic peptide tachykinin NK₂ receptor antagonist. The aim of the trial was to examine the effect of nepadutant on neurokinin A-induced bronchoconstriction in man.

Methods: 12 patients with stable, mild to moderate asthma participated in a double-blind, placebo-controlled crossover trial and received, with intervals of 1 week, MEN11420 2 mg, MEN11420 8 mg and placebo (i.v.). Increasing concentrations of NKA (10^-9 to 10^-6 moles/ml) were inhaled immediately after (d1) and 24 hours after (d2) administration of treatment.

Results: On d1 both MEN11420 2 and 8 mg shifted the dose response curve for neurokinin A to the right (log PC₂₀ FEV₁ neurokinin A [moles/ml]; mean± SEM -6.38±0.26 after 2 mg, -6.11±0.23 after 8 mg, versus -6.95±0.27 after placebo]. On d2 MEN11420 had no effect on neurokinin A-induced bronchoconstriction.

Conclusion: In conclusion, the tachykinin NK₂ receptor antagonist nepadutant significantly inhibits bronchoconstriction induced by neurokinin A in patients with asthma.

Keywords

asthma tachykinins neurokinin A bronchoconstriction NK2 receptor antagonist

References

Advenier, C. , Naline, E. , Toty, L. , Bakdach, H. , Emonds-Alt, X. , Vilain, P. et al. (1992) Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors. Am Rev Respir Dis 146: 1177-1181.

Amadesi, S. , Moreau, J. , Tognetto, M. , Springer, J. , Trevisani, M. , Naline, E. et al. (2001) NK1 receptor stimulation causes contraction and inositol phosphate increase in medium-size human isolated bronchi. Am J Respir Crit Care Med 163: 1206-1211.

Barchasz, E. , Naline, E. , Molimard, M. , Moreau, J. , Georges, O. , Emonds-Alt, X. et al. (1999) Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi. Eur J Pharmacol 379: 87-95.

Catalioto, R. , Criscuoli, M. , Cucchi, P. , Giachetti, A. , Gianotti, D. , Giuliani, S. et al. (1998) MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist. Br J Pharmacol 123: 81-91.

Cheung, D. , Bel, E. , Den Hartigh, J. , Dijkman, J. and Sterk, P. ( 1992) The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo. Am Rev Respir Dis 145: 1275-1280.

Cialdai, C. , Tramontana, M. , Patacchini, R. , Lecci, A. , Catalani, C. , Catalioto, R. et al. (2006) MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist. Eur J Pharmacol 549: 140-148.

Cockroft, D. ( 1977) Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 7: 235-243.

Joos, G. , Germonpré, P. and Pauwels, R. ( 2000) Role of tachykinins in asthma. Allergy 55: 321-337.

Joos, G. and Pauwels, R. ( 2000) Pro-inflammatory effects of substance P: new perspectives for the treatment of airway diseases? Trends Pharmacol Sci 21: 131-133.

10.

Joos, G. , Pauwels, R. and van der Straeten, M. ( 1987) Effect of inhaled substance P and neurokinin A on the airways of normal and asthmatic subjects. Thorax 42: 779-783.

11.

Joos, G. , Vincken, W. , Louis, R. , Schelfhout, V. , Wang, J. , Shaw, M. et al. (2004) Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients. Eur Respi J 23: 76-81.

12.

Lördal, M. , Navalesi, G. , Theodorsson, E. , Maggi, C. and Hellström, P. ( 2001) A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine. Br J Pharmacol 134: 215-223.

13.

Maggi, C. ( 1993) Tachykinin receptors and airway pathophysiology. Eur Respir J 6: 735-742.

14.

Meini, S. , Bellucci, F. , Catalani, C. , Cucchi, P. , Giolitti, A. , Santicioli, P. et al. (2009) Multifaceted approach to determine the antagonist molecular mechanism and interaction of ibodutant at the human tachykinin NK2 receptor . J Pharmacol Exp Ther 329: 486-495.

15.

Naline, E. , Molimard, M. , Regoli, D. , Emonds-Alt, X. , Bellamy, J.F. and Advenier, C. ( 1996) Evidence for functional tachykinin NK1 receptors on human isolated small bronchi. Am J Physiol 271: L763-L767.

16.

Schelfhout, V. , Louis, R. , Lenz, W. , Heyrman, R. , Pauwels, R. and Joos, G. ( 2006) The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma. Pulm Pharmacol Ther 19: 413-418.

17.

Tramontana, M. , Patacchini, R. , Giuliani, S. , Lippi, A. , Lecci, A. , Santicioli, P. et al. (1998) Characterization of the antibronchoconstrictor activity of MEN 11420, a tachykinin NK2 receptor antagonist, in guinea-pigs. Eur J Pharmacol 352: 279-288.

18.

Van Schoor, J. , Joos, G.F. , Chasson, B.L. , Brouard, R.J. and Pauwels, R.A. ( 1998) The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics . Eur Respir J 12: 17-23.