Effect of the long‐acting tachykinin NK 1 receptor antagonist MEN 11467 on tracheal mucus secretion in allergic ferrets

We investigated the effect of MEN 11467 ((1 R ,2 S )‐2‐ N [1( H )indol‐3‐yl‐carbonyl]‐1‐ N ‐{ N α ( p ‐tolylacetyl)‐ N α (methyl)‐ D ‐3‐(2‐naphthyl)alanyl}diaminocyclohexane) on tachykinin‐induced mucus secretion in ferret trachea in vitro and determined its effect on secretion by tracheae from allergic ferrets in response to allergen challenge. Repeated administration of [Sar 9 ,Met(O 2 ) 11 ]‐substance P ([Sar 9 ]SP, 1 μ M ) maintained mucus output above control values for at least 1.75 h. MEN 11467 inhibited secretion in a concentration‐dependent manner with maximal inhibition at 10 μ M and an approximate IC 50 of 0.3 μ M . Inhibition by MEN 11467 (0.1 – 10 μ M ) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar 9 ]SP. In electrically stimulated tracheae, tachykininergic neural secretion was virtually abolished by 1 μ M MEN 11467. In tracheae from ovalbumin‐sensitised animals, repeated administration of ovalbumin maintained mucus output above controls for 1.5 h. MEN 11467 inhibited ovalbumin‐induced secretion in a concentration‐dependent manner, with complete inhibition at 1 μ M . Inhibition by MEN 11467 (1 and 10 μ M ) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. MEN 11467 1 μ M did not affect secretion induced by either acetylcholine or histamine, whereas 10 μ M MEN 11467 did inhibit agonist‐induced secretion. We conclude that, in ferret trachea in vitro , MEN 11467 at concentrations of 0.1 – 1 μ M is a long acting and selective inhibitor of tachykininergic‐induced mucus secretion, and may have therapeutic potential for bronchial hypersecretion associated with allergic conditions, for example in asthma.British Journal of Pharmacology (2001) 132 , 189–196; doi: 10.1038/sj.bjp.0703822