title: 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.
abstract: 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 [Sar(9),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 microg/kg i.v.), microvascular leakage (1 and 3 mg/kg i.p.), and bronchoconstriction (50 and 100 microg/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.
authors.affiliation: Sanofi-Synthélabo Recherche, Montpellier, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Emonds-Alt
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Proietto
authors.forename: Régis
authors.initials: R
authors.lastname: Steinberg
authors.forename: Florence
authors.initials: F
authors.lastname: Oury-Donat
authors.forename: Xavier
authors.initials: X
authors.lastname: Vigé
authors.forename: Pol
authors.initials: P
authors.lastname: Vilain
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.forename: Samira
authors.initials: S
authors.lastname: Daoui
authors.forename: Charles
authors.initials: C
authors.lastname: Advenier
authors.forename: Gérard
authors.initials: G
authors.lastname: Le Fur
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Maffrand
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubrié
authors.forename: Marc
authors.initials: M
authors.lastname: Pascal
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C469681:2-(1-(2-(4-(2-(3,5-bis(trifluoromethyl)phenyl)acetyl)-2-(3,4-dichlorophenyl)-2-morpholinyl)ethyl)-4-piperidinyl)-2-methylpropanamide; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; C085215:SR 140333