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
Document Type
Article
Publication Date
1-1-2010
Abstract
The preclinical characterization of WS-50030 [7-{4-[3-(1Hinden-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.
DOI
10.1124/jpet.109.157388
Montclair State University Digital Commons Citation
Brennan, Julie Adams; Graf, Radka; Grauer, Steven M.; Navarra, Rachel L.; Pulicicchio, Claudine M.; Hughes, Zoë A.; Lin, Qian; Wantuch, Caitlin; Rosenzweig-Lipson, Sharon; Pruthi, Farhana; Lai, Margaret; Smith, Deborah; Goutier, Wouter; Van De Neut, Martina; Robichaud, Albert J.; Rotella, David; Feenstra, Rolf W.; Kruse, Chris; Broqua, Pierre; Beyer, Chad E.; McCreary, Andrew C.; Pausch, Mark H.; and Marquis, Karen L., "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" (2010). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 370.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/370