RT Journal Article SR Electronic T1 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 JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1171 OP 1179 DO 10.1124/jpet.102.040162 VO 303 IS 3 A1 Xavier Emonds-Alt A1 Vincenzo Proietto A1 Régis Steinberg A1 Florence Oury-Donat A1 Xavier Vigé A1 Pol Vilain A1 Emmanuel Naline A1 Samira Daoui A1 Charles Advenier A1 Gérard Le Fur A1 Jean-Pierre Maffrand A1 Philippe Soubrié A1 Marc Pascal YR 2002 UL http://jpet.aspetjournals.org/content/303/3/1171.abstract AB 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 NK1receptors but was less potent on rat and gerbil NK1receptors. 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 NK1receptor-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.