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)-1-N-{(1R,2S)-2-N-[1(H)indol-3-ylcarbonyl]aminocyclohexanecarbony}-1-[N'-methyl-N'-(4-methylphenylacetyl)]diaminoethane, a novel partially retro-inverse pseudo peptide antagonist of tachykinin NK1 receptors. MEN 11149 potently inhibits the binding of [H-3]substance P to tachykinin NK1 sites in IM9 cells (pK(i) = 8.5 +/- 0.1). The compound is highly specific for the human tachykinin NK1 receptors, since it has negligible effects (pK(i) < 6) on the binding of specific ligands to tachykinin NK2, NK3 receptors and a battery of central and peripheral receptors or ion channels. The tachykinin NK1 receptor antagonism of MEN 11149 appears to be insurmountable since, in saturation binding experiments, both K-D and B-max are significantly affected by incubation with the compound (1-30 nM). Ln isolated guinea-pig ileum, MEN 11149 (0.1-100 nM) shifts to the right in a non-parallel way the substance P methyl ester-induced cumulative concentration-response curve with progressive inhibition of the maximal response (pK(B) = 9.6 +/- 0.1). When tested for reversibility at 5 nM in the same preparation, the compound displays a slow dissociation rate compared to the fast dissociation rate with FK888 (N-2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-L-3-(2-naphthyl)alaninamide) at 5 nM. In the same preparation, MEN 11149 (10 mu M) did not affect the cumulative concentration-response curve to acetylcholine. In vivo, MEN 11149 dose dependently antagonizes [Sar(9),Met(O-2)(11)]substance P-induced bronchoconstriction in anaesthetized guinea-pigs (ID50 = 83 +/- 31 nmol/kg i.v.). The duration of the effect exceeds 3 h. MEN 11149 does not affect the bronchoconstriction induced by neurokinin A. The compound dose dependently inhibits [Sar(9),Met(O-2)(11)]substance P-induced plasma protein extravasation in guinea-pig bronchi whether administered intravenously (ID50 = 0.22 +/- 0.02 mu mol/kg) or orally (ID50 = 0.97 +/- 0.21 mu mol/kg). These results demonstrate that MEN 11149 is a potent, highly selective and orally effective insurmountable antagonist of tachykinin NK1 receptors with a long duration of action. (C) 1998 Elsevier Science B.V.