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

We have investigated the pharmacological properties of MEN 11467, a novel p artially retro-inverse peptidomimetic antagonist of tachykinin NK1 receptor s. MEN 11467 potently inhibits the binding of [H-3] substance P (SP) to tac hykinin NK, receptors in the IM9 limphoblastoid cell line (p K-i = 9.4 +/- 0.1). MEN 11467 is highly specific for the human tachykinin NK, receptors, since it has negligible effects (p K-i < 6) on the binding of specific liga nds to tachykinin NK2 or NK3 receptors and to a panel of 30 receptors ion c hannels unrelated to tachykinin receptors. The antagonism exerted by MEN 11 467 at tachykinin NK, receptors is insurmountable in saturation binding exp eriments, both KID and B,ax of SP were significantly reduced by MEN 11467 ( 0.3-10 nM). In the guinea-pig isolated ileum, MEN 11467 (0.03-1 nM) produce d a nonparallel rightward shift of the concentration-response curve to SP m ethylester with a concomitant reduction of the Emax to the agonist (p K-B = 10.7 +/- 0.1). Moreover the antagonist activity of MEN 11467 was hardly re versible despite prolonged washout. In vivo, MEN 11467 produced a long last ing (> 2-3 h) dose-dependent antagonism of bronchoconstriction induced by t he selective tachykinin NK, receptor agonist, [Sar(9), Met(O-2)(11)]SP in a naesthetized guinea-pigs (ID(50)s ' = 29 +/- 5, 31 +/- 12 and 670 +/- 270 m ug/kg, after intravenous, intranasal and intraduodenal administration, resp ectively), without affecting bronchoconstriction induced by methacholine. A fter oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar(9), Met( O-2)(11)] (ID50 = 6.7 +/- 2 mg/kg) or by antigen challenge in sensitized an imals (ID50 = 1.3 mg/kg). After i.v. administration MEN 11467 weakly inhibi ted the GR 73632-induced foot tapping behaviour in gerbil (ED50 = 2.96 +/- 2 mg/kg), indicating a poor ability to block central tachykinin NK, recepto rs. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseuclopeptide antagonist of peripheral tachykinin NK, receptors with a long duration of action. (C) 2001 Harcourt Publishers Ltd.