Molecular Interventions for Bipolar Disorder

描述(由申请人提供)：超过200万美国成年人患有双相情感障碍，约占任何一年18岁及以上人口的1%。目前的治疗方法包括所谓的“情绪稳定剂”、锂和丙戊酸。这两种药物都是相对过时的药物，只有部分有效，并会产生各种不良副作用，包括体重增加。基于对锂分子靶点的持续努力，现在看来，糖原合成酶激酶-3b(GSK-3b)的特定抑制剂可能会模仿情绪稳定剂的治疗作用，因此可能会允许设计出治疗双相情感障碍患者的改进药物。此外，GSK-3酶的促凋亡特性暗示了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，但其中许多还没有在一系列生物学测试中得到充分的表征，学术研究人员也不容易获得这些药物。这些化合物主要是ATP竞争性抑制剂，其激酶活性已在体外确定；在许多情况下，它们的真实的激酶选择性分布和它们的体内作用，包括可能的副作用，仍有待确定。显然，需要新的、选择性的和安全的GSK-3抑制剂作为药理工具和治疗药物，用于各种中枢神经系统疾病，包括各种双相情感障碍，但也包括帕金森病和阿尔茨海默病等。到目前为止，我们已经从星形孢子素的SAR研究中发现了一些NM效力的GSK-3抑制剂。此外，我们还发现其中一些配体在体外能够发挥神经保护作用。我们预计，进一步的研究工作很可能会导致化合物可以推进到临床。为了实现这一目标，我们的目标如下：目标1：利用合理的药物设计原则，进一步扩大和改进我们已经确定的有效的GSK-3抑制剂；将利用电子对接方法辅助选择新的配体用于合成，然后将这些化合物以镁合成到克量；目标2：所有新合成的配体都将在激酶试验中进行测试，以评估它们抑制GSK-3亚型(a和b)的选择性和效力。对于最好的化合物(Kj值和25 nm)，将它们与有限数量的相关激酶，即AKT1/PKBA、CDK2/Cyclin E、CDK3/Cyclin E、CDK5/p25和ICK进行比较，以获得某种程度的激酶选择性；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；目的3：检查最好的GSK-3抑制剂(Ki和lt；25 nM，对其他酶的选择性至少是10倍，并在低微摩尔范围内显示出神经保护作用)，因为它们能够在动物模型中发挥抗抑郁作用以及抗躁狂效果；这一目标将由我们在SquchoGenics Inc.的行为合作者使用他们的专利SmartCube技术实现。

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.