title: Biochemical and pharmacological activities of SSR 146977, a new potent nonpeptide tachykinin NK3 receptor antagonist.
abstract: SSR 146977 is a potent and selective antagonist of the tachykinin NK3 receptor. In Chinese hamster ovary cells expressing the human tachykinin NK3 receptor, SSR 146977 inhibited the binding of radioactive neurokinin B to NK3 receptors (Ki = 0.26 nM), senktide (10 nM) induced inositol monophosphate formation (IC50 = 7.8-13 nM), and intracellular calcium mobilization (IC50 = 10 nM). It antagonized [MePhe7]neurokinin B induced contractions of guinea pig ileum (pA2 = 9.07). Senktide (30 nM) induced firing rate increase of noradrenergic neurons in the guinea pig locus coeruleus and dopaminergic neurons in the guinea pig substantia nigra was also blocked by SSR 146977 (50 and 100 nM, respectively). In vivo, in the respiratory system, SSR 146977 inhibited bronchial hyperresponsiveness to acetylcholine, bronchial microvascular permeability hypersensitivity to histamine (doses of 0.1-1 mg/kg i.p.), and cough (doses of 0.03-1 mg/kg i.p.) provoked by citric acid in guinea pigs. In the central nervous system, SSR 146977 inhibited turning behaviour (ID50 = 0.2 mg/kg i.p. and 0.4 mg/kg p.o.) and prevented the decrease of locomotor activity (10 and 30 mg/kg i.p) mediated by the stimulation of NK3 receptors in gerbils. In guinea pigs, SSR 146977 antagonized senktide-induced acetylcholine release in the hippocampus (0.3 and 1 mg/kg i.p) and norepinephrine release in the prefrontal cortex (0.3 mg/kg i.p.). It also prevented haloperidol-induced increase of the number of spontaneously active dopamine A10 neurons (1 and 3 mg/kg i.p.).
authors.affiliation: Sanofi-Synthelabo Recherche, Montpellier, France. xavier.emonds-alt@sanofi-synthelabo.com
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: Charles
authors.initials: C
authors.lastname: Advenier
authors.forename: Samira
authors.initials: S
authors.lastname: Daoui
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.forename: Christiane
authors.initials: C
authors.lastname: Gueudet
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Michaud
authors.forename: Florence
authors.initials: F
authors.lastname: Oury-Donat
authors.forename: Martine
authors.initials: M
authors.lastname: Poncelet
authors.forename: Pol
authors.initials: P
authors.lastname: Vilain
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; D016466:CHO Cells; D006224:Cricetinae; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D008782:Methylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D015287:Neurokinin B / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D008782:Methylurea Compounds; D010446:Peptide Fragments; D010880:Piperidines; D018042:Receptors, Neurokinin-3; C468909:SSR 146977; C054724:senktide; D013373:Substance P; D015287:Neurokinin B