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. Beyer & 3 others Andrew C. McCreary, Mark H. Pausch, Karen L. Marquis

Research output: Contribution to journalArticleResearchpeer-review

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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title = "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",
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",
number = "1",

}

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 journalArticleResearchpeer-review

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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DO - 10.1124/jpet.109.157388

M3 - Article

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EP - 201

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

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