title: Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents.
abstract: This study characterized the novel neurokinin (NK)(1) antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.
authors.affiliation: Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, Croissy/Seine, Paris, France.
authors.forename: Mauricette
authors.initials: M
authors.lastname: Brocco
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mannoury la Cour
authors.forename: Manuelle
authors.initials: M
authors.lastname: Touzard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Girardon
authors.forename: Sylvie
authors.initials: S
authors.lastname: Veiga
authors.forename: Guillaume
authors.initials: G
authors.lastname: de Nanteuil
authors.forename: Trynke R
authors.initials: TR
authors.lastname: deJong
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005239:Fear / Q000187:drug effects; D005260:Female; D005464:Fluorobenzenes; D005849:Gerbillinae; D007398:Interpersonal Relations; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology*; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: D005464:Fluorobenzenes; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D013373:Substance P; D048049:Extracellular Signal-Regulated MAP Kinases; C534550:vestipitant