Effect of the long‐acting tachykinin NK1 receptor antagonist MEN 11467 on tracheal mucus secretion in allergic ferrets

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Abstract
We investigated the effect of MEN 11467 ((1R,2S)‐2‐N[1(H)indol‐3‐yl‐carbonyl]‐1‐N‐{Nα(p‐tolylacetyl)‐Nα(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 [Sar9,Met(O2)11]‐substance P ([Sar9]SP, 1 μM) 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 μM and an approximate IC50 of 0.3 μM. Inhibition by MEN 11467 (0.1 – 10 μM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar9]SP. In electrically stimulated tracheae, tachykininergic neural secretion was virtually abolished by 1 μM 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 μM. Inhibition by MEN 11467 (1 and 10 μM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. MEN 11467 1 μM did not affect secretion induced by either acetylcholine or histamine, whereas 10 μM MEN 11467 did inhibit agonist‐induced secretion. We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1 – 1 μM 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