title: Identification of a glycogen synthase kinase-3β 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-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.
authors: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA. kozikowa@uic.edu
authors: Alan P
authors: AP
authors: Kozikowski
authors: Hendra
authors: H
authors: Gunosewoyo
authors: Songpo
authors: S
authors: Guo
authors: Irina N
authors: IN
authors: Gaisina
authors: Richard L
authors: RL
authors: Walter
authors: Ariel
authors: A
authors: Ketcherside
authors: Colleen A
authors: CA
authors: McClung
authors: Andrew D
authors: AD
authors: Mesecar
authors: Barbara
authors: B
authors: Caldarone
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D056926:CLOCK Proteins; C538944:Clock protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3