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Title: Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice

Abstract

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-3{beta} (GSK-3{beta}) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3{beta}. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC{sub 50} values in the range of 4 to 680 nM against human GSK-3{beta}. 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{sup -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{sup -1}) and the antipsychotic haloperidol (1 mg kg{sup -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 demonstratesmore » the use of inhibitors of GSK-3{beta} in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3{beta} as a relevant therapeutic target in the identification of new therapies for bipolar patients.« less

Authors:
; ; ; ; ; ; ; ;  [1]
  1. Psychogenics
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1033010
Resource Type:
Journal Article
Journal Name:
ChemMedChem
Additional Journal Information:
Journal Volume: 6; Journal Issue: (9) ; 09, 2011; Journal ID: ISSN 1860-7179
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ABSORPTION; ATTENUATION; DISTRIBUTION; EXCRETION; GLYCOGEN; LITHIUM; METABOLISM; MICE; MUTANTS; MUTATIONS; PATIENTS; PHOSPHOTRANSFERASES; PIPERIDINES; SIDE EFFECTS; TARGETS

Citation Formats

Kozikowski, Alan P, Gunosewoyo, Hendra, Guo, Songpo, Gaisina, Irina N, Walter, Richard L, Ketcherside, Ariel, McClung, Colleen A, Mesecar, Andrew D, Caldarone, Barbara, Purdue), UIC), and UTSMC). Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice. United States: N. p., 2012. Web. doi:10.1002/cmdc.201100188.
Kozikowski, Alan P, Gunosewoyo, Hendra, Guo, Songpo, Gaisina, Irina N, Walter, Richard L, Ketcherside, Ariel, McClung, Colleen A, Mesecar, Andrew D, Caldarone, Barbara, Purdue), UIC), & UTSMC). Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice. United States. https://doi.org/10.1002/cmdc.201100188
Kozikowski, Alan P, Gunosewoyo, Hendra, Guo, Songpo, Gaisina, Irina N, Walter, Richard L, Ketcherside, Ariel, McClung, Colleen A, Mesecar, Andrew D, Caldarone, Barbara, Purdue), UIC), and UTSMC). 2012. "Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice". United States. https://doi.org/10.1002/cmdc.201100188.
@article{osti_1033010,
title = {Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice},
author = {Kozikowski, Alan P and Gunosewoyo, Hendra and Guo, Songpo and Gaisina, Irina N and Walter, Richard L and Ketcherside, Ariel and McClung, Colleen A and Mesecar, Andrew D and Caldarone, Barbara and Purdue) and UIC) and UTSMC)},
abstractNote = {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-3{beta} (GSK-3{beta}) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3{beta}. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC{sub 50} values in the range of 4 to 680 nM against human GSK-3{beta}. 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{sup -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{sup -1}) and the antipsychotic haloperidol (1 mg kg{sup -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-3{beta} in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3{beta} as a relevant therapeutic target in the identification of new therapies for bipolar patients.},
doi = {10.1002/cmdc.201100188},
url = {https://www.osti.gov/biblio/1033010}, journal = {ChemMedChem},
issn = {1860-7179},
number = (9) ; 09, 2011,
volume = 6,
place = {United States},
year = {Wed May 02 00:00:00 EDT 2012},
month = {Wed May 02 00:00:00 EDT 2012}
}