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

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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]aminocyclohexanecarbonyl}-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 [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 KD 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 (pKB=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 (N2-[(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 μM) did not affect the cumulative concentration–response curve to acetylcholine. In vivo, MEN 11149 dose dependently antagonizes [Sar9,Met(O2)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 [Sar9,Met(O2)11]substance P-induced plasma protein extravasation in guinea-pig bronchi whether administered intravenously (ID50=0.22±0.02 μmol/kg) or orally (ID50=0.97±0.21 μmol/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.

Introduction

The undecapeptide substance P belongs, together with neurokinin A and neurokinin B, to the tachykinin family of neuropeptides. These peptides act through stimulation of three major receptor subtypes, termed tachykinin NK1, NK2 and NK3, having preferential affinity for substance P, neurokinin A and neurokinin B, respectively (Regoli et al., 1994; Maggi, 1995). Substance P is expressed and released from primary sensory nerve fibers and elicits a variety of biological responses centrally and peripherally (Maggi et al., 1993). Substance P is thought to be a key mediator for pain perception as well as for neurogenic inflammation (Jancso et al., 1968; Cuello et al., 1993). This latter term indicates the wide range of inflammatory responses (smooth muscle contraction, vasodilatation, increase in vascular permeability, recruitment of inflammatory cells and secretion) that follows the stimulation of the efferent function of these sensory neurons and the consequent release of tachykinins (Otsuka and Yoshioka, 1993). These biological responses induced by substance P are mediated by activation of tachykinin NK1 receptors and therefore it has been suggested that specific and selective antagonists of this receptor could represent a new class of analgesic and/or antiinflammatory substances (Beattie et al., 1995a; Lowe and McLean, 1995).

Our understanding of the biological actions of substance P and the involvement of tachykinin NK1 receptors has progressed significantly following the identification of several non-peptide tachykinin NK1 receptor antagonists with high affinity and selectivity (Snider et al., 1991; Fujii et al., 1992; Emonds-Alt et al., 1993; Beattie et al., 1995b; Gitter et al., 1995; Gardner et al., 1996; McLean et al., 1996). In addition, peptide antagonists of tachykinin NK1 receptor have also been described (Hagan et al., 1991; Morimoto et al., 1992; Hagiwara et al., 1994), although their duration of action is short and their oral efficacy is generally low (Hagan et al., 1991; Fujii et al., 1992; Hagiwara et al., 1992; Hashimoto et al., 1992). We now report on the discovery of MEN 11149, 2-(2-naphthyl)-1-N-{(1R,2S)-2-N-[1(H)indol-3-yl-carbonyl]aminocyclo-hexanecarbonyl}-1-[N′-methyl-N′-(4-methylphenylacetyl)] diaminoethane (Fig. 1), as the prototype of a new class of partially retro-inverse pseudopeptides, characterized by a retro amide bond, a N-methyl gem-diamine moiety and a β-aminocycloalkyl carboxylic acid residue. This compound is the result of a progressive site-modification of the structure of the peptidic antagonist, FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-methyl-N-phenylmethyl-l-3-(2-naphthyl)alaninamide), with the aim to protect the analogue from enzymatic processing by alteration of the peptide backbone and preserving the correct three-dimensional arrangement of the aromatic rings of the molecule, a key requisite for its biological activity (Sisto et al., 1994). The pharmacology of MEN 11149 has been examined in a variety of in vitro and in vivo preparations, in comparison to that of FK 888. In principle it is possible to design a long-acting and orally effective peptidomimetic compound showing a potent and insurmountable selective antagonism for the tachykinin NK1 receptor.

Section snippets

Tachykinin NK1 receptor binding in human lymphoblastoma IM9 cells

Tachykinin NK1 receptor binding was assessed using the human lymphoblastoma IM9 cell line. The IM9 cell line was obtained from the American Type Culture Collection (Rockville, MD) and cultured as previously described (Goso et al., 1994). Binding to IM9 cells was determined by incubating 4×106 cells/tube with 0.3 nM [3H]substance P in the presence of increasing concentrations of MEN 11149 or FK888 for 60 min at room temperature. The reaction was terminated by centrifugation in a Beckman 12

Effect on tachykinin receptors

The affinity of MEN 11149 for the tachykinin NK1 receptor was assessed by measuring the displacement of [3H]substance P binding to human IM9 cells. MEN 11149 inhibited [3H]substance P binding to IM9 cells in a concentration-dependent manner giving a pKi value of 8.5±0.1 (n=6). The pKi value for FK 888 was 8.9±0.2 (n=5).

The nature of MEN 11149 inhibition was studied by Scatchard analysis of specific [3H]substance P binding to IM9 cells in the absence and presence of increasing concentrations

Discussion

MEN 11149 is the prototype of a new class of partially retro-inverse pseudopeptides, structurally related to FK 888. The main modification is the introduction of a β-amino cycloalkyl carboxylic acid residue, aimed at protection of the analogue from enzymatic processing by alteration of the peptide backbone, preserving the correct three-dimensional arrangement of the aromatic rings of the FK 888 molecule, a key requisite for its biological activity (Sisto et al., 1994). The present work

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