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

European Journal of Pharmacology
R CirilloS Manzini

Abstract

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]aminocy clohexanecarbonyl]-1-[N'-methyl-N'-(4-methylphenylacetyl)]di aminoethane, a novel partially retro-inverse pseudo peptide antagonist of tachykinin NK1 receptors. MEN 11149 potently inhibits the binding of [3H]substance P to tachykinin NK1 sites in IM9 cells (pKi = 8.5 +/- 0.1). The compound is highly specific for the human tachykinin NK1 receptors, since it has negligible effects (pKi < 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 Bmax 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 (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 ...Continue Reading

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Citations

Jan 12, 2002·British Journal of Pharmacology·Francesca BellucciCarlo Alberto Maggi
Feb 20, 2014·Medicinal Research Reviews·Dong GuoLaura H Heitman
Jun 19, 2007·The Journal of Pharmacology and Experimental Therapeutics·Erik LindströmGeorges Vauquelin
Sep 14, 2018·Current Medicinal Chemistry·Charlene Gadais, Steven Ballet

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