214487-46-4

Tachykinin NK ₁ receptor

MEN11467 potently inhibits the binding of [ ³ H] substance P (SP) to tachykinin NK ₁ receptors in the IM9 limphoblastoid cell line (pK _i =9.4±0.1). MEN11467 is highly specific for the human tachykinin NK ₁ receptors, since it has negligible effects (pK _i <6) on the binding of specific ligands to tachykinin NK ₂ or NK ₃ receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN11467 at tachykinin NK ₁ receptors is insurmountable in saturation binding experiments, both K _D and B _max of SP are significantly reduced by MEN11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN11467 (0.03-1 nM) produces a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the E _max to the agonist (pK _B =10.7±0.1). Moreover the antagonist activity of MEN11467 is hardly reversible despite prolonged washout. The pseudopeptide tachykinin NK ₁ receptor antagonist, MEN11467 is used to study tachykininergic involvement in antigen-induced mucus secretion in ferret trachea in vitro. MEN11467 (1 nM-10 μM) inhibits [Sar ⁹ ]SP-induced ³⁵ SO ₄ , output in a concentration-dependent manner with an approximate IC ₅₀ of 0.3  μM.

MEN11467 produces a long lasting (>2-3 h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK ₁ receptor agonist, [Sar ⁹ , Met(O ₂ ) ¹¹ ]SP in anaesthetized guinea-pigs (ID ₅₀ s=29±5, 31±12 and 670±270 μg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN11467 produces a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar ⁹ , Met(O ₂ ) ¹¹ ] (ID ₅₀ = 6.7±2 mg/kg) or by antigen challenge in sensitized animals (ID ₅₀ =1.3 mg/kg). After i.v. administration MEN11467 weakly inhibits the GR 73632-induced foot tapping behaviour in gerbil (ED ₅₀ =2.96±2 mg/kg), indicating a poor ability to block central tachykinin NK ₁ receptors. Treatment with MEN11467 (1 mmol/kg twice weekly for 2 weeks) results in a temporary growth arrest of the U373 MG xenograft that last for about 10 days until the last MEN11467 administration (TVI%=56). Thereafter, the tumor start to regrow. MEN11467 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 s.c. treatment with a higher MEN11467 dose (1.7 mmol/kg at five times a week for 6 weeks) completely inhibits the growth of 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%.