title: WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: a novel dopamine D2 receptor partial agonist/serotonin reuptake inhibitor with preclinical antipsychotic-like and antidepressant-like activity.
abstract: The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.1 nM), potent D(2) partial agonist activity (EC(50), 0.38 nM; E(max), 30%), and complete block of the serotonin transporter (IC(50), 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID(50), 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D(2) partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D(2) receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA. brennaj2@wyeth.com
authors.forename: Julie A
authors.initials: JA
authors.lastname: Brennan
authors.forename: Radka
authors.initials: R
authors.lastname: Graf
authors.forename: Steven M
authors.initials: SM
authors.lastname: Grauer
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Navarra
authors.forename: Claudine M
authors.initials: CM
authors.lastname: Pulicicchio
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: Qian
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authors.lastname: Lin
authors.forename: Caitlin
authors.initials: C
authors.lastname: Wantuch
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: Farhana
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authors.lastname: Pruthi
authors.forename: Margaret
authors.initials: M
authors.lastname: Lai
authors.forename: Deborah
authors.initials: D
authors.lastname: Smith
authors.forename: Wouter
authors.initials: W
authors.lastname: Goutier
authors.forename: Martina
authors.initials: M
authors.lastname: van de Neut
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.forename: David
authors.initials: D
authors.lastname: Rotella
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Feenstra
authors.forename: Chris
authors.initials: C
authors.lastname: Kruse
authors.forename: Pierre
authors.initials: P
authors.lastname: Broqua
authors.forename: Chad E
authors.initials: CE
authors.lastname: Beyer
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.forename: Mark H
authors.initials: MH
authors.lastname: Pausch
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007192:Indenes / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D012701:Serotonin / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001583:Benzoxazoles; D004298:Dopamine; D018491:Dopamine Agonists; D007192:Indenes; D017448:Receptors, Dopamine D2; D012701:Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C546598:7-(4-(3-(1H-inden-3-yl)propyl)piperazin-1-yl)-1,3-benzoxazol-2(3H)-one