BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia

Yona Geffen; Abraham Nudelman; Irit Gil-Ad; Ada Rephaeli; Mei Huang; Kinneret Savitsky; Leah Klapper; Ilan Winkler; Herbert Y. Meltzer; Abraham Weizman

doi:10.1016/j.euroneuro.2008.07.002

BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia

Yona Geffen, Abraham Nudelman, Irit Gil-Ad, Ada Rephaeli, Mei Huang, Kinneret Savitsky, Leah Klapper, Ilan Winkler, Herbert Y. Meltzer, Abraham Weizman

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Reduced brain γ-amino-butyric acid (GABA) participates in the pathogenesis of schizophrenia. GABA scarcely penetrates the brain. We evaluated the pharmacological properties of BL-1020, a novel GABA ester of perphenazine. Oral BL-1020 or perphenazine were assessed in acute and subchronic schizophrenia rat models. Catalepsy, serum prolactin, receptor binding profile and cortical (PFC), hippocampal (Hip) and dopamine (DA) levels were determined. Radioactive [¹⁴C] labeled BL-1020 was used for pharmacokinetics (PK). Acute and subchronic treatment with BL-1020 antagonized amphetamine-induced hyperactivity, with significantly lower catalepsy and sedation compared to equimolar perphenazine. At the same time, BL-1020 increased DA release in the PFC and Hip. BL-1020 and perphenazine stimulated prolactin secretion equally. BL-1020 displayed strong DA and serotonin (5HT) receptor inhibition (D_2L K_iz = 0.066 nM, D_2S K_i = 0.062 nM, 5-HT_2A K_i = 0.21 nM). PK data revealed that BL-1020 penetrated the brain. Conclusions: The advantages of BL-1020 for treatment of schizophrenia stem from its being a DA/5HT antagonist and a GABAergic agsonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation.

Original language	English
Pages (from-to)	1-13
Number of pages	13
Journal	European Neuropsychopharmacology
Volume	19
Issue number	1
DOIs	https://doi.org/10.1016/j.euroneuro.2008.07.002
State	Published - Jan 2009

Bibliographical note

Funding Information:
The study was supported by grant provided by BiolineRX, and by the Chief Scientist of Israel.

Funding Information:
We would like to acknowledge Shlomit Halachmi M.D., Ph.D. for her contribution to this study. The generous support for this work provided by the “Marcus Center for Pharmaceutical and Medicinal Chemistry” at Bar Ilan University, is gratefully acknowledged. Additional funding was provided by the Office of the Chief Scientist, Israel Ministry of Industry, Trade & Labor. We wish to thank Igor Tarasenko for his skilled technical contribution.

Funding

The study was supported by grant provided by BiolineRX, and by the Chief Scientist of Israel. We would like to acknowledge Shlomit Halachmi M.D., Ph.D. for her contribution to this study. The generous support for this work provided by the “Marcus Center for Pharmaceutical and Medicinal Chemistry” at Bar Ilan University, is gratefully acknowledged. Additional funding was provided by the Office of the Chief Scientist, Israel Ministry of Industry, Trade & Labor. We wish to thank Igor Tarasenko for his skilled technical contribution.

Funders	Funder number
BiolineRx
Chief Scientist of Israel
Office of the Chief Scientist, Israel Ministry of Industry, Trade & Labor
Bar-Ilan University

Keywords

Antipsychotics
Dopamine
GABA
Perphenazine
Schizophrenia
Serotonin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.euroneuro.2008.07.002

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title = "BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia",

abstract = "Reduced brain γ-amino-butyric acid (GABA) participates in the pathogenesis of schizophrenia. GABA scarcely penetrates the brain. We evaluated the pharmacological properties of BL-1020, a novel GABA ester of perphenazine. Oral BL-1020 or perphenazine were assessed in acute and subchronic schizophrenia rat models. Catalepsy, serum prolactin, receptor binding profile and cortical (PFC), hippocampal (Hip) and dopamine (DA) levels were determined. Radioactive [14C] labeled BL-1020 was used for pharmacokinetics (PK). Acute and subchronic treatment with BL-1020 antagonized amphetamine-induced hyperactivity, with significantly lower catalepsy and sedation compared to equimolar perphenazine. At the same time, BL-1020 increased DA release in the PFC and Hip. BL-1020 and perphenazine stimulated prolactin secretion equally. BL-1020 displayed strong DA and serotonin (5HT) receptor inhibition (D2L Kiz = 0.066 nM, D2S Ki = 0.062 nM, 5-HT2A Ki = 0.21 nM). PK data revealed that BL-1020 penetrated the brain. Conclusions: The advantages of BL-1020 for treatment of schizophrenia stem from its being a DA/5HT antagonist and a GABAergic agsonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation.",

keywords = "Antipsychotics, Dopamine, GABA, Perphenazine, Schizophrenia, Serotonin",

author = "Yona Geffen and Abraham Nudelman and Irit Gil-Ad and Ada Rephaeli and Mei Huang and Kinneret Savitsky and Leah Klapper and Ilan Winkler and Meltzer, {Herbert Y.} and Abraham Weizman",

note = "Funding Information: The study was supported by grant provided by BiolineRX, and by the Chief Scientist of Israel. Funding Information: We would like to acknowledge Shlomit Halachmi M.D., Ph.D. for her contribution to this study. The generous support for this work provided by the “Marcus Center for Pharmaceutical and Medicinal Chemistry” at Bar Ilan University, is gratefully acknowledged. Additional funding was provided by the Office of the Chief Scientist, Israel Ministry of Industry, Trade & Labor. We wish to thank Igor Tarasenko for his skilled technical contribution.",

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doi = "10.1016/j.euroneuro.2008.07.002",

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AU - Nudelman, Abraham

AU - Gil-Ad, Irit

AU - Rephaeli, Ada

AU - Huang, Mei

AU - Savitsky, Kinneret

AU - Klapper, Leah

AU - Winkler, Ilan

AU - Meltzer, Herbert Y.

AU - Weizman, Abraham

N1 - Funding Information: The study was supported by grant provided by BiolineRX, and by the Chief Scientist of Israel. Funding Information: We would like to acknowledge Shlomit Halachmi M.D., Ph.D. for her contribution to this study. The generous support for this work provided by the “Marcus Center for Pharmaceutical and Medicinal Chemistry” at Bar Ilan University, is gratefully acknowledged. Additional funding was provided by the Office of the Chief Scientist, Israel Ministry of Industry, Trade & Labor. We wish to thank Igor Tarasenko for his skilled technical contribution.

PY - 2009/1

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N2 - Reduced brain γ-amino-butyric acid (GABA) participates in the pathogenesis of schizophrenia. GABA scarcely penetrates the brain. We evaluated the pharmacological properties of BL-1020, a novel GABA ester of perphenazine. Oral BL-1020 or perphenazine were assessed in acute and subchronic schizophrenia rat models. Catalepsy, serum prolactin, receptor binding profile and cortical (PFC), hippocampal (Hip) and dopamine (DA) levels were determined. Radioactive [14C] labeled BL-1020 was used for pharmacokinetics (PK). Acute and subchronic treatment with BL-1020 antagonized amphetamine-induced hyperactivity, with significantly lower catalepsy and sedation compared to equimolar perphenazine. At the same time, BL-1020 increased DA release in the PFC and Hip. BL-1020 and perphenazine stimulated prolactin secretion equally. BL-1020 displayed strong DA and serotonin (5HT) receptor inhibition (D2L Kiz = 0.066 nM, D2S Ki = 0.062 nM, 5-HT2A Ki = 0.21 nM). PK data revealed that BL-1020 penetrated the brain. Conclusions: The advantages of BL-1020 for treatment of schizophrenia stem from its being a DA/5HT antagonist and a GABAergic agsonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation.

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BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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