Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice
Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called “mood-stabilizing drugs”, such as lithium and valproate that are relatively dated drugs with various known side eff...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
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Wiley-VCH Verlag GmbH & Co. KGaA
2011
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| Online Access: | http://hdl.handle.net/20.500.11937/30218 |
| _version_ | 1848753025507655680 |
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| author | Kozikowski, A. Gunosewoyo, Hendra Guo, S. Gaisina, I. Walter, R. Ketcherside, A. McClung, C. Mesecar, A. Caldarone, B. |
| author_facet | Kozikowski, A. Gunosewoyo, Hendra Guo, S. Gaisina, I. Walter, R. Ketcherside, A. McClung, C. Mesecar, A. Caldarone, B. |
| author_sort | Kozikowski, A. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called “mood-stabilizing drugs”, such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3β (GSK-3β) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3β. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC50 values in the range of 4 to 680 nM against human GSK-3β. One of these compounds exhibits reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25 mg kg−1 resulted in the attenuation of hyperactivity in amphetamine/chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400 mg kg−1) and the antipsychotic haloperidol (1 mg kg−1). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3β in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3β as a relevant therapeutic target in the identification of new therapies for bipolar patients. |
| first_indexed | 2025-11-14T08:17:57Z |
| format | Journal Article |
| id | curtin-20.500.11937-30218 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T08:17:57Z |
| publishDate | 2011 |
| publisher | Wiley-VCH Verlag GmbH & Co. KGaA |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-302182018-03-29T09:08:51Z Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice Kozikowski, A. Gunosewoyo, Hendra Guo, S. Gaisina, I. Walter, R. Ketcherside, A. McClung, C. Mesecar, A. Caldarone, B. GSK-3 inhibitors circadian rhythms bipolar disorder antimanic agents CLOCK mutant mice Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called “mood-stabilizing drugs”, such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3β (GSK-3β) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3β. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC50 values in the range of 4 to 680 nM against human GSK-3β. One of these compounds exhibits reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25 mg kg−1 resulted in the attenuation of hyperactivity in amphetamine/chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400 mg kg−1) and the antipsychotic haloperidol (1 mg kg−1). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3β in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3β as a relevant therapeutic target in the identification of new therapies for bipolar patients. 2011 Journal Article http://hdl.handle.net/20.500.11937/30218 10.1002/cmdc.201100188 Wiley-VCH Verlag GmbH & Co. KGaA restricted |
| spellingShingle | GSK-3 inhibitors circadian rhythms bipolar disorder antimanic agents CLOCK mutant mice Kozikowski, A. Gunosewoyo, Hendra Guo, S. Gaisina, I. Walter, R. Ketcherside, A. McClung, C. Mesecar, A. Caldarone, B. Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice |
| title | Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice |
| title_full | Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice |
| title_fullStr | Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice |
| title_full_unstemmed | Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice |
| title_short | Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice |
| title_sort | identification of a glycogen synthase kinase-3β inhibitor that attenuates hyperactivity in clock mutant mice |
| topic | GSK-3 inhibitors circadian rhythms bipolar disorder antimanic agents CLOCK mutant mice |
| url | http://hdl.handle.net/20.500.11937/30218 |