title: Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist.
abstract: The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA. ringr@wyeth.com
authors.forename: Robert H
authors.initials: RH
authors.lastname: Ring
authors.forename: Lee E
authors.initials: LE
authors.lastname: Schechter
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Leonard
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Platt
authors.forename: Radka
authors.initials: R
authors.lastname: Graf
authors.forename: Steven
authors.initials: S
authors.lastname: Grauer
authors.forename: Claudine
authors.initials: C
authors.lastname: Pulicicchio
authors.forename: Lynn
authors.initials: L
authors.lastname: Resnick
authors.forename: Zia
authors.initials: Z
authors.lastname: Rahman
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Sukoff Rizzo
authors.forename: Bin
authors.initials: B
authors.lastname: Luo
authors.forename: Chad E
authors.initials: CE
authors.lastname: Beyer
authors.forename: Sheree F
authors.initials: SF
authors.lastname: Logue
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005334:Fever / Q000188:drug therapy / Q000209:etiology; D019417:Hindlimb Suspension / Q000379:methods; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects; D010121:Oxytocin / Q000819:agonists / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000819:agonists*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications
chemical_list: C547280:4-(3,5-dihydroxybenzyl)-N-(2-methyl-4-((1-methyl-4,10-dihydropyrazolo(3,4-b)(1,5)benzodiazepin-5(1H)-yl)carbonyl)benzyl)piperazine-1-carboxamide; D014151:Anti-Anxiety Agents; D011720:Pyrazoles; D018045:Receptors, Oxytocin; D001569:Benzodiazepines; D010121:Oxytocin