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 11 149, N'-methyl-N'-(4-methylphenylacetyl)]diaminoethane, a novel partia lly retro-inverse pseudo peptide antagonist of tachykinin NK1 receptor s. MEN 11149 potently inhibits the binding of [H-3]substance P to tach ykinin NK1 sites in IM9 cells (pK(i) = 8.5 +/- 0.1). The compound is h ighly specific for the human tachykinin NK1 receptors, since it has ne gligible effects (pK(i) < 6) on the binding of specific ligands to tac hykinin NK2, NK3 receptors and a battery of central and peripheral rec eptors or ion channels. The tachykinin NK1 receptor antagonism of MEN 11149 appears to be insurmountable since, in saturation binding experi ments, both K-D and B-max are significantly affected by incubation wit h 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 met hyl ester-induced cumulative concentration-response curve with progres sive inhibition of the maximal response (pK(B) = 9.6 +/- 0.1). When te sted for reversibility at 5 nM in the same preparation, the compound d isplays a slow dissociation rate compared to the fast dissociation rat e with FK888 methyl-N-phenylmethyl-L-3-(2-naphthyl)alaninamide) at 5 n M. In the same preparation, MEN 11149 (10 mu M) did not affect the cum ulative concentration-response curve to acetylcholine. In vivo, MEN 11 149 dose dependently antagonizes [Sar(9),Met(O-2)(11)]substance P-indu ced 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 compo und dose dependently inhibits [Sar(9),Met(O-2)(11)]substance P-induced plasma protein extravasation in guinea-pig bronchi whether administer ed 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 antagonis t of tachykinin NK1 receptors with a long duration of action. (C) 1998 Elsevier Science B.V.