RT Journal Article
SR Electronic
T1 WS-50030 [7-{4-[3-(1<em>H</em>-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3<em>H</em>)-one]: A Novel Dopamine D<sub>2</sub> Receptor Partial Agonist/Serotonin Reuptake Inhibitor with Preclinical Antipsychotic-Like and Antidepressant-Like Activity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 190
OP 201
DO 10.1124/jpet.109.157388
VO 332
IS 1
A1 Julie A. Brennan
A1 Radka Graf
A1 Steven M. Grauer
A1 Rachel L. Navarra
A1 Claudine M. Pulicicchio
A1 Zoë A. Hughes
A1 Qian Lin
A1 Caitlin Wantuch
A1 Sharon Rosenzweig-Lipson
A1 Farhana Pruthi
A1 Margaret Lai
A1 Deborah Smith
A1 Wouter Goutier
A1 Martina van de Neut
A1 Albert J. Robichaud
A1 David Rotella
A1 Rolf W. Feenstra
A1 Chris Kruse
A1 Pierre Broqua
A1 Chad E. Beyer
A1 Andrew C. McCreary
A1 Mark H. Pausch
A1 Karen L. Marquis
YR 2010
UL http://jpet.aspetjournals.org/content/332/1/190.abstract
AB 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 D2 receptor (D2L Ki, 4.0 nM) and serotonin transporter (Ki, 7.1 nM), potent D2 partial agonist activity (EC50, 0.38 nM; Emax, 30%), and complete block of the serotonin transporter (IC50, 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 (ID50, 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 D2 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 D2 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.© 2010 by The American Society for Pharmacology and Experimental Therapeutics