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Chemical Compound Review

Nepadutant     (2S)-2-[[(3S,6S,9S,12S)-12- [[(2S)-3-[[(2R...

Synonyms: MEN-11,420, LS-55819, DCL000894, DNC000550, MEN 11420, ...
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Disease relevance of Nepadutant


Psychiatry related information on Nepadutant

  • In the same preparation MEN 11420 (0.1 microM) blocked (apparent pK(B) = 8.2) the potentiation of spontaneous motor activity produced by the NK2 receptor-selective agonist [betaAla8]NKA(4-10) [5].
  • MEN 11420 (100 microg kg-1) increased significantly pain threshold (20.5 +/- 1.2 vs. 17.0 +/- 0.8 mm Hg) but did not modify gastric volumes at the three doses tested [6].

High impact information on Nepadutant

  • The result is the discovery of receptor antagonists with a higher affinity than nepadutant for the hNK-2 receptor [7].
  • In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients [8].
  • NaHS-induced contractile effects were totally prevented by the simultaneous incubation with tachykinin NK(1) (GR 82334; 10 microm) and NK(2) (nepadutant; 0.3 microm) receptor-selective antagonists [9].
  • In contrast, nepadutant significantly decreased (70%) the number of Fos-positive neurons in dorsal horn, DCM, and SPN spinal cord regions and significantly decreased (75%) the number of Jun-positive DRG neurons after TNBS-induced irritation of the colon [1].
  • Nepadutant pharmacokinetics and dose-effect relationships as tachykinin NK2 receptor antagonist are altered by intestinal inflammation in rodent models [10].

Biological context of Nepadutant


Anatomical context of Nepadutant

  • However, in both preparations, the effect of MEN 11420 was reverted by washout and an apparent pK(B) of 10.2+/-0.14, n = 9, and 9.8+/-0.15, n = 9, was calculated in the hamster trachea and mouse urinary bladder, respectively [13].
  • 5. MEN 11420 showed low affinity (pK(B) < 6) at guinea-pig and rat tachykinin NK1 (guinea-pig ileum and rat urinary bladder) and NK3 (guinea-pig ileum and rat portal vein) receptors [13].
  • 4. In the rabbit isolated pulmonary artery and rat urinary bladder MEN 11420 potently and competitively antagonized tachykinin NK2 receptor-mediated contractions (pK(B) = 8.6+/-0.07, n = 10, and 9.0+/-0.04, n = 12; Schild plot slope = -1.06 (95% c.l. = -1.3; -0.8) and -1.17 (95% c.l. = -1.3; -1.0), respectively) [13].
  • 2. MEN 11420 competitively bound with high affinity to the human NK2 receptor stably transfected in CHO cells, displacing radiolabelled [125I]-neurokinin A and [3H]-SR 48968 with Ki values of 2.5+/-0.7 nM (n = 6) and 2.6+/-0.4 nM (n = 3), respectively [13].
  • 1. In isolated tissue experiments, neurokinin A (NKA) produced concentration-dependent contraction of human and guinea-pig ureter (pD2 = 6.7 and 7.2, respectively); an effect greatly reduced (>80% inhibition) by the tachykinin NK2 receptor-selective antagonist MEN 11420 (0.1 microM) [5].

Associations of Nepadutant with other chemical compounds

  • On the whole, the affinities (potency and selectivity) showed by MEN 11420 for different tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN 10627 [13].
  • SR 140,333 (1 micromol./kg., i.v.) neither modified urodynamic parameters in controls and in PS + LPS-treated rats nor altered the effect of MEN 11,420 in these groups [14].
  • Bilateral electrical stimulation of the vagi (20 Hz for 20 s) induced a bronchoconstriction that was dose-dependently inhibited by i.v. MEN 11420, SR 48968 and MEN 10627 [15].
  • The selective tachykinin NK2 receptor antagonist, nepadutant (10 nM-1 microM) produced a concentration-dependent and even inhibition of both contraction and PGE2 release induced by [betaAla8]NKA(4-10) [16].
  • In sucrose gap, MEN 11420 concentration-dependently inhibited both depolarization (IC50 0.34 microM) and contraction (IC50 = 0.32 microM) produced by [beta Ala8]NKA (4-10) (0.3 microM for 10 s) in the guinea-pig colon without affecting the corresponding responses produced by [Sar9]SP sulfone [17].

Gene context of Nepadutant

  • We have characterized the action of the novel, water-soluble, tachykinin NK2 receptor antagonist MEN 11420 ([Asn(2-AcNH-beta-D-Glc)-Asp-Trp-Phe-Dap-Leu] c(2 beta-5 beta)) on the circular muscle of the guinea-pig and human colon in vitro and on the guinea-pig colon in vivo [17].
  • In organ bath experiments on guinea-pig colon MEN 11420 produced a concentration-dependent rightward shift of the concentration-response curve to the NK2 receptor selective agonist, [beta Ala8]neurokinin A (NKA) (4-10) with a pKB value of 8 [17].
  • MEN 11,420, a peptide tachykinin NK2 receptor antagonist, was administered before cystometries or, in a separate group of animals, during cystometries [14].
  • Contractions to SP were significantly reduced by RP67580 but not affected by nepadutant or SR142801 [18].
  • Increased Fos expression following LUT irritation or a sham operation in wild type mice was also significantly reduced by pretreatment with the NK2 antagonist, MEN 11420, but Fos expression in mutant mice was not altered by the antagonist [19].

Analytical, diagnostic and therapeutic context of Nepadutant


  1. Effect of nepadutant, a neurokinin 2 tachykinin receptor antagonist, on immediate-early gene expression after trinitrobenzenesulfonic acid-induced colitis in the rat. Birder, L.A., Kiss, S., de Groat, W.C., Lecci, A., Maggi, C.A. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  2. Evidence of a peripheral role of neurokinins in detrusor hyperreflexia: a further study of selective tachykinin antagonists in chronic spinal injured rats. Abdel-Gawad, M., Dion, S.B., Elhilali, M.M. J. Urol. (2001) [Pubmed]
  3. Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea-pigs. Cutrufo, C., Evangelista, S., Cirillo, R., Ciucci, A., Conte, B., Lopez, G., Manzini, S., Maggi, C.A. Neuropeptides (2000) [Pubmed]
  4. Tachykinin receptors antagonists: from research to clinic. Quartara, L., Altamura, M. Current drug targets. (2006) [Pubmed]
  5. Excitatory motor and electrical effects produced by tachykinins in the human and guinea-pig isolated ureter and guinea-pig renal pelvis. Patacchini, R., Santicioli, P., Zagorodnyuk, V., Lazzeri, M., Turini, D., Maggi, C.A. Br. J. Pharmacol. (1998) [Pubmed]
  6. Role of NK2 receptors in gastric barosensitivity and in experimental ileus in rats. Toulouse, M., Fioramonti, J., Maggi, C., Buéno, L. Neurogastroenterol. Motil. (2001) [Pubmed]
  7. Monocyclic human tachykinin NK-2 receptor antagonists as evolution of a potent bicyclic antagonist: QSAR and site-directed mutagenesis studies. Giolitti, A., Altamura, M., Bellucci, F., Giannotti, D., Meini, S., Patacchini, R., Rotondaro, L., Zappitelli, S., Maggi, C.A. J. Med. Chem. (2002) [Pubmed]
  8. Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome. Lecci, A., Capriati, A., Maggi, C.A. Br. J. Pharmacol. (2004) [Pubmed]
  9. Hydrogen sulfide (H2S) stimulates capsaicin-sensitive primary afferent neurons in the rat urinary bladder. Patacchini, R., Santicioli, P., Giuliani, S., Maggi, C.A. Br. J. Pharmacol. (2004) [Pubmed]
  10. Nepadutant pharmacokinetics and dose-effect relationships as tachykinin NK2 receptor antagonist are altered by intestinal inflammation in rodent models. Lecci, A., Carini, F., Tramontana, M., D'Aranno, V., Marinoni, E., Crea, A., Bueno, L., Fioramonti, J., Criscuoli, M., Giuliani, S., Maggi, C.A. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  11. Characterization of receptors mediating contraction induced by tachykinins in the guinea-pig isolated common bile duct. Patacchini, R., Barthó, L., Maggi, C.A. Br. J. Pharmacol. (1997) [Pubmed]
  12. A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine. Lördal, M., Navalesi, G., Theodorsson, E., Maggi, C.A., Hellström, P.M. Br. J. Pharmacol. (2001) [Pubmed]
  13. MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist. Catalioto, R.M., Criscuoli, M., Cucchi, P., Giachetti, A., Gianotti, D., Giuliani, S., Lecci, A., Lippi, A., Patacchini, R., Quartara, L., Renzetti, A.R., Tramontana, M., Arcamone, F., Maggi, C.A. Br. J. Pharmacol. (1998) [Pubmed]
  14. Effect of tachykinin NK2 receptor blockade on detrusor hyperreflexia induced by bacterial toxin in rats. Lecci, A., Tramontana, M., Giuliani, S., Criscuoli, M., Maggi, C.A. J. Urol. (1998) [Pubmed]
  15. Characterization of the antibronchoconstrictor activity of MEN 11420, a tachykinin NK2 receptor antagonist, in guinea-pigs. Tramontana, M., Patacchini, R., Giuliani, S., Lippi, A., Lecci, A., Santicioli, P., Criscuoli, M., Maggi, C.A. Eur. J. Pharmacol. (1998) [Pubmed]
  16. Role of prostanoids in the contraction induced by a tachykinin NK2 receptor agonist in the hamster urinary bladder. Tramontana, M., Catalioto, R.M., Lecci, A., Maggi, C.A. Naunyn Schmiedebergs Arch. Pharmacol. (2000) [Pubmed]
  17. MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the guinea-pig and human colon. Santicioli, P., Giuliani, S., Patacchini, R., Tramontana, M., Criscuoli, M., Maggi, C.A. Naunyn Schmiedebergs Arch. Pharmacol. (1997) [Pubmed]
  18. Functional characterisation of tachykinin receptors in the circular muscle layer of the mouse ileum. De Schepper, H.U., De Winter, B.Y., Seerden, T.C., Herman, A.G., Pelckmans, P.A., De Man, J.G. Regul. Pept. (2005) [Pubmed]
  19. Impaired response to chemical irritation of the urinary tract in mice with disruption of the preprotachykinin gene. Kiss, S., Yoshiyama, M., Cao, Y.Q., Basbaum, A.I., de Groat, W.C., Lecci, A., Maggi, C.A., Birder, L.A. Neurosci. Lett. (2001) [Pubmed]
  20. MEN 11,420, a peptide tachykinin NK2 receptor antagonist, reduces motor responses induced by the intravesical administration of capsaicin in vivo. Lecci, A., Giuliani, S., Tramontana, M., Criscuoli, M., Maggi, C.A. Naunyn Schmiedebergs Arch. Pharmacol. (1997) [Pubmed]
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