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

Julie Adams 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, Rolf W. Feenstra, Chris Kruse, Pierre Broqua, Chad E. BeyerAndrew C. McCreary, Mark H. Pausch, Karen L. Marquis

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)190-201
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number1
DOIs
StatePublished - 1 Jan 2010

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Dopamine D2 Receptors
Serotonin Uptake Inhibitors
Antidepressive Agents
Antipsychotic Agents
Serotonin Plasma Membrane Transport Proteins
Serotonin
Treatment-Resistant Depressive Disorder
Catalepsy
7-(4-(3-(1H-inden-3-yl)propyl)piperazin-1-yl)-1,3-benzoxazol-2(3H)-one
Apomorphine
Oxidopamine
Major Depressive Disorder
Substantia Nigra
Prefrontal Cortex
Bipolar Disorder
Inhibitory Concentration 50
Schizophrenia
Aripiprazole

Cite this

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. ; 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. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 332, No. 1. pp. 190-201.
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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.",
author = "Brennan, {Julie Adams} and Radka Graf and Grauer, {Steven M.} and Navarra, {Rachel L.} and Pulicicchio, {Claudine M.} and Hughes, {Zo{\"e} A.} and Qian Lin and Caitlin Wantuch and Sharon Rosenzweig-Lipson and Farhana Pruthi and Margaret Lai and Deborah Smith and Wouter Goutier and {Van De Neut}, Martina and Robichaud, {Albert J.} and David Rotella and Feenstra, {Rolf W.} and Chris Kruse and Pierre Broqua and Beyer, {Chad E.} and McCreary, {Andrew C.} and Pausch, {Mark H.} and Marquis, {Karen L.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1124/jpet.109.157388",
language = "English",
volume = "332",
pages = "190--201",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
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Brennan, JA, Graf, R, Grauer, SM, Navarra, RL, Pulicicchio, CM, Hughes, ZA, Lin, Q, Wantuch, C, Rosenzweig-Lipson, S, Pruthi, F, Lai, M, Smith, D, Goutier, W, Van De Neut, M, Robichaud, AJ, Rotella, D, Feenstra, RW, Kruse, C, Broqua, P, Beyer, CE, McCreary, AC, Pausch, MH & Marquis, KL 2010, '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', Journal of Pharmacology and Experimental Therapeutics, vol. 332, no. 1, pp. 190-201. https://doi.org/10.1124/jpet.109.157388

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. / 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.; Marquis, Karen L.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 332, No. 1, 01.01.2010, p. 190-201.

Research output: Contribution to journalArticle

TY - JOUR

T1 - WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol- 2(3H)-one]

T2 - A novel dopamine D2 receptor partial agonist/serotonin reuptake inhibitor with preclinical antipsychotic-like and antidepressant-like activity

AU - Brennan, Julie Adams

AU - Graf, Radka

AU - Grauer, Steven M.

AU - Navarra, Rachel L.

AU - Pulicicchio, Claudine M.

AU - Hughes, Zoë A.

AU - Lin, Qian

AU - Wantuch, Caitlin

AU - Rosenzweig-Lipson, Sharon

AU - Pruthi, Farhana

AU - Lai, Margaret

AU - Smith, Deborah

AU - Goutier, Wouter

AU - Van De Neut, Martina

AU - Robichaud, Albert J.

AU - Rotella, David

AU - Feenstra, Rolf W.

AU - Kruse, Chris

AU - Broqua, Pierre

AU - Beyer, Chad E.

AU - McCreary, Andrew C.

AU - Pausch, Mark H.

AU - Marquis, Karen L.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

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