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: II. Neurochemical and behavioral characterization.
abstract: 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 new nonpeptide tachykinin neurokinin 1 (NK1) receptor antagonist, was evaluated against the neurochemical, electrophysiological, and behavioral effects provoked by direct activation of brain tachykinin NK1 receptors or by stress in guinea pigs. SSR240600 (0.1-10 mg/kg i.p. or p.o.) antagonized the excitatory effect of i.c.v. infusion of [Sar(9),Met(O2)(11)]substance P (SP) on the release of acetylcholine in the striatum of anesthetized and awake guinea pigs. This antagonistic action was still observed after repeated administration of SSR240600 (5 days, 10 mg/kg p.o., once a day). SSR240600 (10 mg/kg i.p.) inhibited the phosphorylation of the cAMP response element-binding protein in various brain regions induced by i.c.v. administration of [Sar9,Met(O2)(11)]SP. In slice preparations, neuronal firing of the locus coeruleus (LC) neurons elicited by the application of [Sar9,Met(O2)(11)]SP was suppressed by SSR240600 at 100 nM. Norepinephrine release in the prefrontal cortex, elicited either by an intra-LC application of [Sar9,Met(O2)(11)]SP or by an i.c.v administration of corticotropin-releasing factor, was reduced by SSR240600 (0.3-1 mg/kg and 1-10 mg/kg i.p., respectively). SSR240600 (1-10 mg/kg i.p.) inhibited vocalizations induced in adult guinea pigs by an i.c.v. administration of the NK1 receptor agonist, GR73632 [D-Ala-[L-Pro9,Me-Leu8]substance P(7-11)]. Furthermore, SSR240600 (1-10 mg/kg i.p.) inhibited distress vocalizations produced in guinea pig pups by maternal separation. SSR240600 also reduced maternal separation-induced increase in the number of neurons displaying NK1 receptor internalization in the amygdala. Finally, SSR240600 counteracted the increase in body temperature induced by isolation stress. In conclusion, SSR240600 is able to antagonize various NK1 receptor-mediated as well as stress-mediated effects in the guinea pig.
authors.affiliation: C.N.S. Research Department, Sanofi-Synthélabo Recherche, Montpellier, France. regis.steinberg@sanofi-synthelabo.com
authors.forename: Régis
authors.initials: R
authors.lastname: Steinberg
authors.forename: Richard
authors.initials: R
authors.lastname: Alonso
authors.forename: Liliane
authors.initials: L
authors.lastname: Rouquier
authors.forename: Christophe
authors.initials: C
authors.lastname: Desvignes
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Michaud
authors.forename: Annie
authors.initials: A
authors.lastname: Cudennec
authors.forename: Mireille
authors.initials: M
authors.lastname: Jung
authors.forename: Jacques
authors.initials: J
authors.lastname: Simiand
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Xavier
authors.initials: X
authors.lastname: Emonds-Alt
authors.forename: Gérard
authors.initials: G
authors.lastname: Le Fur
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubrié
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D014828:Vocalization, Animal / Q000187:drug effects* / Q000502:physiology
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; D017362:Cyclic AMP Response Element-Binding Protein; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D000109:Acetylcholine; D009638:Norepinephrine