Identification of a glycogen synthase kinase-3β inhibitor that attenuates hyperactivity in CLOCK mutant mice

Alan P. Kozikowski, Hendra Gunosewoyo, Songpo Guo, Irina N. Gaisina, Richard L. Walter, Ariel Ketcherside, Colleen A. McClung, Andrew D. Mesecar, Barbara Caldarone

Research output: Contribution to journalArticlepeer-review

Abstract

Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5million 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 IC 50 values in the range of 4 to 680nM 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 25mgkg -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 (400mgkg -1) and the antipsychotic haloperidol (1mgkg -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.

Original languageEnglish (US)
Pages (from-to)1593-1602
Number of pages10
JournalChemMedChem
Volume6
Issue number9
DOIs
StatePublished - Sep 5 2011

Keywords

  • Antimanic agents
  • Bipolar disorder
  • CLOCK mutant mice
  • Circadian rhythms
  • GSK-3 inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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