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.

Autors:	Julie A Brennan, Radka Graf, Steven M Grauer, Rachel L Navarra, Claudine M Pulicicchio, Zoë A Hughes, Qian Lin, Caitlin Wantuch, Sharon Rosenzweig-Lipson, Farhana Pruthi, Margaret Lai, Deborah Smith, Wouter Goutier, Martina van de Neut, Albert J Robichaud, David Rotella
Idioma:	Eng.
Data:	2009-12-21
Revista:	The Journal of pharmacology and experimental therapeutics (1521-0103)
Lliurament:	J Pharmacol Exp Ther. 2010 Jan;332(1):190-201
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.
Copyright:	The Journal of pharmacology and experimental therapeutics Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA. brennaj2 wyeth.com
Full text:	DOI - The Journal of pharmacology and experimental therapeutics (DOI) HighWire Press - HTML (amb subscripció)
Temes:	Animals, Antidepressive Agents, Antipsychotic Agents, Avoidance Learning, Behavior, Animal, Benzoxazoles, Brain, CHO Cells, Cricetinae, Cricetulus, Dopamine, Dopamine Agonists, Drug Evaluation, Preclinical, Humans, Indenes, Male, Mice, Mice, Inbred Strains, Microdialysis, Motor Activity, Protein Binding, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptor, Serotonin, 5-HT1A, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2B, Receptors, Dopamine D2, Serotonin, Serotonin Uptake Inhibitors, Transfection