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

1 We investigated the effect of MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbo nyl]-1-N-{N-alpha(p-tolylacetyl) -N-alpha(methyl)-D-3-(2-naphthyl)alanyl}di aminocyclohexane) on tachykinin-induced mucus secretion in ferret trachea i n vitro and determined its effect on secretion by tracheae from allergic fe rrets in response to allergen challenge. 2 Repeated administration of [Sar(9),Met(O-2)(11)]-substance P ([Sar(9)]SP, 1 muM) maintained mucus output above control values for at least 1.75 h. M EN 11467 inhibited secretion in a concentration-dependent manner with maxim al inhibition at 10 muM and an approximate IC50 of 0.3 muM. Inhibition by M EN 11467 (0.1-10 muM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar(9)]SP. 3 In electrically stimulated tracheae, tachykininergic neural secretion was virtually abolished by 1 muM MEN 11467. 4 In tracheae from ovalbumin-sensitised animals, repeated administration of ovalbumin maintained mucus output above controls for 1.5 h. MEN 11467 inhi bited ovalbumin-induced secretion in a concentration-dependent manner, with complete inhibition at 1 muM. Inhibition by MEN 11467 (1 and 10 muM) was m aintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. 5 MEN 11467 1 muM did not affect secretion induced by either acetylcholine or histamine, whereas 10 muM MEN 11467 did inhibit agonist-induced secretio n. 6 We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1-1 muM is a long acting and selective inhibitor of tachykininergic-i nduced mucus secretion, and may have therapeutic potential for bronchial hy persecretion associated with allergic conditions, for example in asthma.