Molecular Interventions for Bipolar Disorder

双相情感障碍的分子干预

基本信息

批准号：
7528127
负责人：
alan P. kozikowski
金额：
$ 43.89万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-18 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7528127
关键词：
Accounting Adult Adverse effects Age Alzheimer&apos s Disease Alzheimer&apos 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 Cell Culture Techniques Cells Central Nervous System Diseases Chemicals Chemistry Chicago Chlordiazepoxide Cholesterol Clinic Collaborations Complement Complex Computer Simulation Cyclin E Data Developed Countries Developing 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

项目摘要

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，约1％的年龄在任何一年中年龄在18岁及以上的人口，患有双相情感障碍。当前的处理包括所谓的“情绪稳定剂”，即锂和丙戊酸。两者都是相对过时的药物，仅部分有效，并产生各种不良副作用，包括体重增加。基于持续了解锂分子靶标的努力，现在看来酶糖原合酶激酶激酶-3b（GSK-3B）的特定抑制剂可能模仿情绪稳定剂的治疗作用，因此可能允许设计改进的治疗双极疾病患者的药物。此外，GSK-3酶的促凋亡特性表明可能使用诸如神经保护剂等抑制剂。神经保护可能进一步有助于情绪障碍药物的治疗功效。目前有许多合成GSK-3抑制剂目前可用，但是其中许多抑制剂尚未在一系列生物学测试中充分表征，学术研究人员也不容易获得。这些化合物在很大程度上是ATP竞争性抑制剂，其激酶活性已在体外确定。在许多情况下，它们的真实激酶选择性谱及其体内作用（包括可能的副作用）仍有待确定。显然，需要新颖，选择性和安全的GSK-3抑制剂作为药理学工具，也需要作为用于各种CNS疾病的治疗方法，包括各种双相疾病，但也是帕金森氏病，以及阿尔茨海默氏病，仅举几例。迄今为止，我们已经确定了一些NM效力GSK-3抑制剂，这些抑制剂从我们的星形孢菌素研究中得出。此外，我们发现其中一些配体能够在体外发挥神经保护作用。我们预计，进一步的研究工作很可能导致可以将其前进到诊所的化合物。为了实现这一目标，我们的目标如下：目标1：进一步扩展和改进我们已经使用理性药物设计原理已经确定的有效GSK-3抑制剂；通过在硅对接方法中使用新的合成配体的新配体和这些化合物将有助于以毫克合成至革兰氏量；目标2：所有新合成的配体将在激酶测定中进行测试，以评估其选择性和效力以抑制GSK-3同工型（a和b）。对于最佳化合物（KJ值<25 nm），请与数量有限的相关激酶（即AKT1/PKBA，CDK2/Cyclin E，CDK3/Cyclin E，CDK5/P25和ICK）相介质，以获得一定的量度。通过检查细胞培养实验中的神经保护作用，进一步表征了体外作用的选择性配体。 AIM 3：检查最佳GSK-3抑制剂（Ki <25 nm，其选择性至少对其他激酶的选择性至少为10倍，并且在低微压范围内显示出神经保护作用），以便在动物模型中发挥抗抑郁作用以及抗疫苗作用的能力；我们的行为合作者将使用专利的SmartCube技术来实现此目标。