Pharmacology of the peptidomimetic, MEN 11149, a new potent, selective and orally effective tachykinin NK1 receptor antagonist

In this study we investigated the pharmacological properties of MEN 11149, 2- 2-naphthyl -1N-1 R,2S -2-N- 1 H indol-3x 4 w XXŽ. xylcarbonyl aminocyclohexanecarbonyl -1N -methyl-N - 4-methylphenylacetyl diaminoethane, a novel partially retro-inverse pseudo w3 x peptide antagonist of tachykinin NK receptors. MEN 11149 potently inhibits the binding of H substance P to tachykinin NK sites in 1 1 Ž.IM9 cells p K s8.5"0.1 . The compound is highly specific for the human tachykinin NK receptors, since it has negligible effects i 1 Ž. pK -6 on the binding of specific ligands to tachykinin NK , NK receptors and a battery of central and peripheral receptors or ion i 23 channels. The tachykinin NK receptor antagonism of MEN 11149 appears to be insurmountable since, in saturation binding experiments, 1 Ž.both K and B are significantly affected by incubation with the compound 1–30 nM . In isolated guinea-pig ileum, MEN 11149 D max Ž. 0.1–100 nM shifts to the right in a non-parallel way the substance P methyl ester-induced cumulative concentration–response curve Ž.with progressive inhibition of the maximal response p K s9.6"0.1 . When tested for reversibility at 5 nM in the same preparation, the B Ž 2 wŽ . Žcompound displays a slow dissociation rate compared to the fast dissociation rate with FK888 N -4 R -4-hydroxy-1- 1-methyl-1H-in. x Ž . . Ž dol-3-yl carbonyl-L-prolyl -N-methyl-N-phenylmethyl-L-3- 2-naphthyl alaninamide at 5 nM. In the same preparation, MEN 11149 10 . m M did not affect the cumulative concentration–response curve to acetylcholine. In vivo, MEN 11149 dose dependently antagonizes w 9 Ž. 11x Ž. Sar ,Met O substance P-induced bronchoconstriction in anaesthetized guinea-pigs ID s83"31 nmolrkg i.v. . The duration of 2 50 the effect exceeds 3 h. MEN 11149 does not affect the bronchoconstriction induced by neurokinin A. The compound dose dependently w 9 Ž. 11x inhibits Sar ,Met O substance P-induced plasma protein extravasation in guinea-pig bronchi whether administered intravenously 2 Ž . Ž . ID s0.22"0.02 m molrkg or orally ID s0.97"0.21 m molrkg . These results demonstrate that MEN 11149 is a potent, highly50 50 selective and orally effective insurmountable antagonist of tachykinin NK receptors with a long duration of action.