Abstract
1. We investigated the effect of MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N-[N(alpha)(p-tolylacetyl)-N(alpha)(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. 2. Repeated administration of [Sar(9),Met(O(2))(11)]-substance P ([Sar(9)]SP, 1 microM) 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 microM and an approximate IC(50) of 0.3 microM. Inhibition by MEN 11467 (0.1--10 microM) 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 microM MEN 11467. 4. 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 microM. Inhibition by MEN 11467 (1 and 10 microM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. 5. MEN 11467 1 microM did not affect secretion induced by either acetylcholine or histamine, whereas 10 microM MEN 11467 did inhibit agonist-induced secretion. 6. We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1--1 microM 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.