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Current treatment regimes include the so\u2010called \u201cmood\u2010stabilizing drugs\u201d, such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase\u20103\u03b2 (GSK\u20103\u03b2) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK\u20103\u03b2. We designed a series of second generation benzofuran\u20103\u2010yl\u2010(indol\u20103\u2010yl)maleimides containing a piperidine ring that possess IC<jats:sub>50<\/jats:sub> values in the range of 4 to 680\u2005n<jats:sc>M<\/jats:sc> against human GSK\u20103\u03b2. 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\u2005mg\u2009kg<jats:sup>\u22121<\/jats:sup> resulted in the attenuation of hyperactivity in amphetamine\/chlordiazepoxide\u2010induced manic\u2010like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400\u2005mg\u2009kg<jats:sup>\u22121<\/jats:sup>) and the antipsychotic haloperidol (1\u2005mg\u2009kg<jats:sup>\u22121<\/jats:sup>). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the <jats:italic>CLOCK<\/jats:italic> gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK\u20103\u03b2 in the treatment of manic episodes of bipolar\/mood disorders, thus further validating GSK\u20103\u03b2 as a relevant therapeutic target in the identification of new therapies for bipolar patients.<\/jats:p>","DOI":"10.1002\/cmdc.201100188","type":"journal-article","created":{"date-parts":[[2011,7,5]],"date-time":"2011-07-05T12:00:29Z","timestamp":1309867229000},"page":"1593-1602","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Identification of a Glycogen Synthase Kinase\u20103\u03b2 Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice"],"prefix":"10.1002","volume":"6","author":[{"given":"Alan P.","family":"Kozikowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendra","family":"Gunosewoyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songpo","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina N.","family":"Gaisina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Ketcherside","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen A.","family":"McClung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Mesecar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Caldarone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,7,5]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1980.tb06059.x"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00384"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4914(01)02266-3"},{"key":"e_1_2_6_5_2","unstructured":"\u00a0"},{"key":"e_1_2_6_6_2","doi-asserted-by":"crossref","first-page":"11074","DOI":"10.1073\/pnas.190297597","volume":"97","author":"Bhat R. 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