Pharmacology of the peptidomimetic, MEN 11149, a new potent, selective and orally effective tachykinin NK 1 receptor antagonist

Abstract

In this study we investigated the pharmacological properties of MEN 11149, 2-(2-naphthyl)-1- N-{(1 R,2 S)-2- N-[1(H)indol-3-ylcarbonyl]aminocyclohexanecarbonyl}-1-[ N′-methyl- N′-(4-methylphenylacetyl)]diaminoethane, a novel partially retro-inverse pseudo peptide antagonist of tachykinin NK 1 receptors. MEN 11149 potently inhibits the binding of [ 3 H ]substance P to tachykinin NK 1 sites in IM9 cells (p K i=8.5±0.1). The compound is highly specific for the human tachykinin NK 1 receptors, since it has negligible effects (p K i<6) on the binding of specific ligands to tachykinin NK 2, NK 3 receptors and a battery of central and peripheral receptors or ion channels. The tachykinin NK 1 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). In 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 (p K 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-[(4 R)-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 μM) 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 (ID 50=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 (ID 50=0.22±0.02 μmol/kg) or orally (ID 50=0.97±0.21 μmol/kg). These results demonstrate that MEN 11149 is a potent, highly selective and orally effective insurmountable antagonist of tachykinin NK 1 receptors with a long duration of action.