Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents.
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.
Brocco
Mauricette
M
Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, Croissy/Seine, Paris, France.
Dekeyne
Anne
A
Mannoury la Cour
Clotilde
C
Touzard
Manuelle
M
Girardon
Sylvie
S
Veiga
Sylvie
S
de Nanteuil
Guillaume
G
deJong
Trynke R
TR
Olivier
Berend
B
Millan
Mark J
MJ
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
D005464:Fluorobenzenes; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D013373:Substance P; D048049:Extracellular Signal-Regulated MAP Kinases; C534550:vestipitant