Disease relevance of Nepadutant

• These findings indicate that nepadutant suppresses the responses of colonic afferent neurons to nociceptive stimuli and that NK2 receptor antagonists may be beneficial in the treatment of sensory symptoms of colitis [1].
• Accordingly, we investigated the effect of a selective neurokinin (NK) 2 receptor antagonist, nepadutant, on proto-oncogene expression in the L(6)-S(1) spinal cord as well as in dorsal root ganglion (DRG) neurons after either non-noxious colorectal distension (CRD) or trinitrobenzenesulfonic acid (TNBS)-induced colitis in the adult rat [1].
• We investigated the selective peptide tachykinin antagonists MEN 11420 and GR 82334 of NK-2 and NK-1 receptors, respectively, in a chronic rat model of detrusor hyperreflexia after suprasacral spinal cord injury [2].
• Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea-pigs [3].
• Other clinical candidates (for central nervous system disorders: osanetant, talnetant and saredutant; for irritable bowel syndrome: nepadutant and saredutant) are in advanced clinical phase [4].

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

• A new series of monocyclic pseudopeptidic tachykinin NK-2 receptor antagonists has been derived from nepadutant with the help of site-directed mutagenesis studies and QSAR models [7].
• In the castor oil model, the oral/intraduodenal bioavailability of nepadutant was also determined [10].
• MEN 11420 (30-300 nM), a novel potent NK2 receptor antagonist, potently antagonized [beta Ala8]NKA (4-10), with competitive kinetics (pKB = 8.25 +/- 0.08; n = 12: Schild plot slope = -0.90; 95% c.l. = -1.4; -0.35) [11].
• Nepadutant had no significant effect on proto-oncogene expression induced by CRD in either spinal cord neurons or DRG neurons [1].
• 7. In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects [12].

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

• Oral administration of nepadutant, in nanomolar or subnanomolar dosage, reduced diarrhea induced by bacterial toxins in mice [10].
• Fifteen minutes before gastric distension or laparotomy, the animals received MEN 11420 (10, 100 or 200 microg kg-1 intravenously) or saline [6].
• MEN 11,420 (100 nmol/kg, i.v.) did not modify motor responses induced by the intravesical administration of saline [20].

References