MEN11467 is a novel, orally available, potent and selective peptidomimetic tachykinin NK 1 receptor antagonist for the study of acute colon cancer.

NK1 receptor:9.4 (pKi), [Sar9]-SP-induced 35SO4 output:0.3 μM

MEN11467 potently inhibits the binding of [3H] substance P (SP) to tachykinin NK1 receptors in the IM9 lymphoblastoid cell line (pKi=9.4±0.1) and is highly specific for human tachykinin NK1 receptors, showing negligible effects (pKi<6) on NK2, NK3 receptors, and 30 other ion channels. In saturation binding experiments, MEN11467's antagonism at tachykinin NK1 receptors is insurmountable, significantly reducing KD and Bmax of SP concentration-dependently (0.3-10 nM). In the guinea-pig isolated ileum, MEN11467 (0.03-1 nM) causes a nonparallel rightward shift of the SP methylester concentration-response curve and reduces the agonist's Emax (pKB=10.7±0.1), with the antagonist activity being hardly reversible despite prolonged washout[1]. In ferret trachea in vitro studies, MEN11467 (1 nM-10 μM) inhibits [Sar9]SP-induced 35SO4 output concentration-dependently, with an approximate IC50 of 0.3 μM[3], highlighting its use in studying tachykininergic involvement in antigen-induced mucus secretion.

MEN11467 produces a long-lasting (>2-3 h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK1 receptor agonist, [Sar9, Met(O2)11]SP, in anaesthetized guinea-pigs (ID50s=29±5, 31±12, and 670±270 μg/kg after intravenous, intranasal, and intraduodenal administration, respectively). This effect is observed without affecting bronchoconstriction induced by methacholine. Following oral administration, MEN11467 produces a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar9, Met(O2)11] (ID50= 6.7±2 mg/kg) or by antigen challenge in sensitized animals (ID50=1.3 mg/kg). Upon intravenous administration, MEN11467 weakly inhibits the GR 73632-induced foot-tapping behavior in gerbils (ED50=2.96±2 mg/kg), indicating a poor ability to block central tachykinin NK1 receptors[1].
Treatment with MEN11467 (1 mmol/kg twice weekly for 2 weeks) results in a temporary growth arrest of the U373 MG xenograft that lasts for about 10 days until the last MEN11467 administration (TVI%=56). Thereafter, the tumor starts to regrow. MEN11467's anti-tumor activity is partially reverted by the simultaneous administration of an equimolar dose of exogenous substance P (SP), suggesting the specificity of tachykinin NK1 receptor activation in glioma growth. Prolonged subcutaneous treatment with a higher MEN11467 dose (1.7 mmol/kg at five times a week for 6 weeks) completely inhibits the growth of the U373 MG tumor for the entire length of the experiment, even following administration of a low exogenous SP dose. After 6 weeks, the tumor mass is not increased compared to the untreated control with TVI%=96%[2].