Vol. 303, Issue 3, 1171-1179, December 2002

SSR240600 [(R)-2-(1-{2-[4-{2-[3,5-Bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}- 4-piperidinyl)-2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the Tachykinin Neurokinin-1 Receptor: I. Biochemical and Pharmacological Characterization

Xavier Emonds-Alt, Vincenzo Proietto, Régis Steinberg, Florence Oury-Donat, Xavier Vigé, Pol Vilain, Emmanuel Naline, Samira Daoui, Charles Advenier, Gérard Le Fur, Jean-Pierre Maffrand, Philippe Soubrié and Marc Pascal

Sanofi-Synthélabo Recherche, Montpellier, France (X.E.-A., V.P., R.S., F.O-D., X.V., P.V., G.L., J.-P.M., P.S., M.P.) and Faculté de Médecine Paris-Ouest, Paris, France (E.N., S.D., C.A.)

The biochemical and pharmacological properties of a novel antagonist of the tachykinin neurokinin 1 (NK₁) receptor, SSR240600 [(R)-2-(1-{2-[4-{2-[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}-4-piperidinyl)-2-methylpropanamide], were evaluated. SSR240600 inhibited the binding of radioactive substance P to tachykinin NK₁ receptors in human lymphoblastic IM9 cells (K_i = 0.0061 nM), human astrocytoma U373MG cells (K_i = 0.10 nM), and human brain cortex (IC₅₀ = 0.017 nM). It also showed subnanomolar affinity for guinea pig NK₁ receptors but was less potent on rat and gerbil NK₁ receptors. SSR240600 inhibited [Sar⁹,Met(O₂)¹¹]substance P-induced inositol monophosphate formation in human astrocytoma U373MG cells with an IC₅₀ value of 0.66 nM (agonist concentration of 100 nM). It also antagonized substance P-induced contractions of isolated human small bronchi with a pIC₅₀ value of 8.6 (agonist concentration of 100 nM). The compound was >100- to 1000-fold more selective for tachykinin NK₁ receptors versus tachykinin NK₂ or NK₃ receptors as evaluated in binding and in vitro functional assays. In vivo antagonistic activity of SSR240600 was demonstrated on tachykinin NK₁ receptor-mediated hypotension in dogs (3 and 10 µg/kg i.v.), microvascular leakage (1 and 3 mg/kg i.p.), and bronchoconstriction (50 and 100 µg/kg i.v.) in guinea pigs. It also prevented citric acid-induced cough in guinea pigs (1-10 mg/kg i.p.), an animal model in which central endogenous tachykinins are suspected to play a major role. In conclusion, SSR240600 is a new, potent, and centrally active antagonist of the tachykinin NK₁ receptor, able to antagonize various NK₁ receptor-mediated pharmacological effects in the periphery and in the central nervous system.