TY - JOUR 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 SP - 190 LP - 201 DO - 10.1124/jpet.109.157388 VL - 332 IS - 1 AU - Julie A. Brennan AU - Radka Graf AU - Steven M. Grauer AU - Rachel L. Navarra AU - Claudine M. Pulicicchio AU - Zoë A. Hughes AU - Qian Lin AU - Caitlin Wantuch AU - Sharon Rosenzweig-Lipson AU - Farhana Pruthi AU - Margaret Lai AU - Deborah Smith AU - Wouter Goutier AU - Martina van de Neut AU - Albert J. Robichaud AU - David Rotella AU - Rolf W. Feenstra AU - Chris Kruse AU - Pierre Broqua AU - Chad E. Beyer AU - Andrew C. McCreary AU - Mark H. Pausch AU - Karen L. Marquis Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/332/1/190.abstract N2 - 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 ER -