Molecular Interventions for Bipolar Disorder

双相情感障碍的分子干预

• 批准号: 8010220
• 负责人: alan P. kozikowski
• 金额: $ 44.09万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-18 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010220
• 关键词: AKT1 gene; Accounting; Adult; Adverse effects; Age; Alzheimer' s Disease; Alzheimer' s disease model; American; Amphetamines; Animal Model; Animals; Antidepressive Agents; Antipsychotic Agents; Apoptotic; Area; Behavior; Behavioral; Behavioral Assay; Benzofurans; Biochemistry; Biological; Biological Assay; Biological Testing; Bipolar Disorder; CDK2 gene; CDK3 gene; CDK5 gene; Cell Culture Techniques; Cell model; Central Nervous System Diseases; Chemicals; Chemistry; Chicago; Chlordiazepoxide; Cholesterol; Clinic; Collaborations; Complement; Complex; Computer Simulation; Cyclin E; Data; Developed Countries; Disease; Docking; Dose; Drug Design; Drug Kinetics; Drug resistance; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Family; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Goals; Human; In Vitro; Indazoles; Indoles; Industry; Institution; Intervention; Intuition; Laboratories; Lead; Legal patent; Ligands; Lithium; Major Depressive Disorder; Maleimides; Malignant Neoplasms; Manic; Marketing; Measures; Medicine; Mental disorders; Methods; Modification; Molecular; Molecular Models; Molecular Target; Mood Disorders; Mood stabilizers; Motor Activity; Names; Neurodegenerative Disorders; Neuroprotective Agents; Obsessive-Compulsive Disorder; Parkinson Disease; Pathway interactions; Patients; Pennsylvania; Pharmaceutical Preparations; Phosphotransferases; Physiologic pulse; Population; Process; Property; Protein Isoforms; Protein Kinase; Recombinants; Research; Research Personnel; Resolution; Schizophrenia; Screening procedure; Services; Side; Specificity; Staurosporine; Stem cells; Structure; Suicide; Swimming; System; Technology; Testing; Therapeutic; Toxicology; Traumatic Brain Injury; Treatment Efficacy; United States; Valproic Acid; Weight Gain; Work; analog; atorvastatin; base; behavioral pharmacology; burden of illness; combat; cost; depressive symptoms; design; disability; drug candidate; drug development; drug discovery; experience; improved; in vivo; inhibitor/antagonist; kinase inhibitor; man; molecular modeling; multidisciplinary; neuroprotection; novel; programs; research study; statistics; tool

DESCRIPTION (provided by applicant): More than 2 million American adults, or about 1 percent of the population age 18 and older in any given year, have bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3b (GSK-3b) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest a potential use of such inhibitors as neuroprotective agents. Neuroprotection may further contribute to the therapeutic efficacy of mood disorder drugs. A number of synthetic GSK-3 inhibitors are now currently available but many of these have not been fully characterized in a battery of biological tests, nor are they readily available to academic researchers. These compounds are largely ATP competitive inhibitors whose kinase activity has been determined in vitro; in many cases their true kinase selectivity profiles and their in vivo action including possible side-effects remain to be established. Clearly, novel, selective and safe GSK-3 inhibitors are needed as both pharmacological tools and as therapeutics for application to a variety of CNS disorders, including various bipolar disorders, but also Parkinson's disease, and Alzheimer's disease to name a few. To date, we have already identified some nM potency GSK-3 inhibitors that emerged from our SAR studies of staurosporine. Moreover, we have found that some of these ligands are able to exert a neuroprotective action in vitro. We anticipate that further research efforts may well lead to compounds that can be advanced to the clinic. To achieve this goal, our aims are as follow: AIM 1: Further expand and improve upon the potent GSK-3 inhibitors we have already identified using rational drug design principles; the selection of new ligands for synthesis will be aided by the use of in silico docking methods and these compounds then synthesized in mg to gram amounts; AIM 2: All newly synthesized ligands will be tested in the kinase assays to evaluate their selectivity and potency to inhibit the GSK-3 isoforms (both a and b). For the best compounds (Kj values < 25 nM), profile them against a limited number of related kinases, namely AKT1/PKBa, CDK2/cyclin E, CDK3/cyclin E, CDK5/p25, and ICK to obtain some measure of kinase selectivity; further characterize selective ligands for in vitro effects by examining their neuroprotective action in cell culture experiments; AIM 3: Examine the effects of the best GSK-3 inhibitors (Ki < 25 nM with a selectivity of at least 10-fold against other kinases and showing a neuroprotective action in the low micromolar range) for their ability to exert both an antidepressant action as well as anti-manic effects in animal models; this aim will be carried out by our behavioral collaborators at PsychoGenics Inc. using their patented SmartCube technology.

描述（由申请人提供）：超过200万美国成年人，或约1%的人口年龄在18岁及以上的任何一年，有双相情感障碍。目前的治疗方法包括所谓的“情绪稳定剂”、锂和丙戊酸。两者都是相对过时的药物，只有部分有效，并产生各种不良副作用，包括体重增加。基于对锂的分子靶点的持续努力，现在看来，糖原合成酶激酶-3b（GSK-3b）的特异性抑制剂可能模拟情绪稳定剂的治疗作用，因此可能允许设计用于治疗双相情感障碍患者的改进药物。此外，GSK-3酶的促细胞凋亡特性表明这种抑制剂作为神经保护剂的潜在用途。神经保护可能进一步有助于情绪障碍药物的治疗效果。目前有许多合成的GSK-3抑制剂，但其中许多尚未在一系列生物学测试中得到充分表征，也不容易为学术研究人员所用。这些化合物主要是ATP竞争性抑制剂，其激酶活性已在体外测定;在许多情况下，其真实的激酶选择性特征及其体内作用（包括可能的副作用）仍有待确定。显然，需要新型、选择性和安全的GSK-3抑制剂作为药理学工具和治疗药物，用于治疗各种中枢神经系统疾病，包括各种双相情感障碍，还有帕金森病和阿尔茨海默病等。到目前为止，我们已经确定了一些nM的效力GSK-3抑制剂，出现在我们的SAR研究的星形孢菌素。此外，我们发现这些配体中的一些能够在体外发挥神经保护作用。我们预计，进一步的研究工作可能会导致化合物，可以先进的临床。为了实现这一目标，我们的目标如下：目的1：进一步扩展和改进我们已经使用合理的药物设计原则鉴定的有效GSK-3抑制剂;通过使用计算机对接方法来辅助选择用于合成的新配体，然后以mg至g的量合成这些化合物;目的2：将在激酶试验中检测所有新合成的配体，以评价其抑制GSK-3亚型（a和B）的选择性和效力。为了最好的化合物（Ki值< 25 nM），针对有限数量的相关激酶（即AKT 1/PKBa、CDK 2/细胞周期蛋白E、CDK 3/细胞周期蛋白E、CDK 5/p25和ICK）对它们进行分析，以获得激酶选择性的一些量度;通过在细胞培养实验中检查它们的神经保护作用，进一步表征选择性配体的体外作用; AIM 3：检查最佳GSK-3抑制剂的效果（Ki < 25 nM，对其他激酶的选择性为至少10倍，在低微摩尔范围内显示神经保护作用），在动物模型中发挥抗抑郁作用以及抗躁狂作用的能力;这一目标将由我们在PsychoGenics公司的行为合作者来实现。使用他们的智能魔方专利技术

项目成果

Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis.

• DOI: 10.1021/jm400511s
• 发表时间: 2013-06-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Gunosewoyo H;Midzak A;Gaisina IN;Sabath EV;Fedolak A;Hanania T;Brunner D;Papadopoulos V;Kozikowski AP
• 通讯作者: Kozikowski AP