Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK1 receptor antagonist

Abstract

We have investigated the pharmacological properties of MEN 11467, a novel partially retro-inverse peptidomimetic antagonist of tachykinin NK1 receptors. MEN 11467 potently inhibits the binding of [3H] substance P (SP) to tachykinin NK1 receptors in the IM9 limphoblastoid cell line (pKi = 9.4 ± 0.1). MEN 11467 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 or NK3 receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN 11467 at tachykinin NK1 receptors is insurmountable in saturation binding experiments, both KD and Bmax of SP were significantly reduced by MEN 11467 (0.3–10nM). In the guinea-pig isolated ileum, MEN 11467 (0.03–1nM) produced a nonparallel rightward shift of the concentration–response curve to SP methylester with a concomitant reduction of the Emax to the agonist (pKB = 10.7 ± 0.1). Moreover the antagonist activity of MEN 11467 was hardly reversible despite prolonged washout. In vivo, MEN 11467 produced a long lasting (> 2–3h) 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±270μg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar9, Met(O2)11] (ID50 = 6.7 ± 2mg/kg) or by antigen challenge in sensitized animals (ID50 = 1.3mg/kg). After i.v. administration MEN 11467 weakly inhibited the GR 73632-induced foot tapping behaviour in gerbil (ED50 = 2.96 ± 2mg/kg), indicating a poor ability to block central tachykinin NK1 receptors. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseudopeptide antagonist of peripheral tachykinin NK1 receptors with a long duration of action.