Molecular Interventions for Bipolar Disorder

描述（由申请人提供）：超过200万美国成年人，或任何一年18岁及以上人口的1%，患有双相情感障碍。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，仅部分有效，并产生各种不良副作用，包括体重增加。基于对锂的分子靶标的持续研究，现在看来糖原合成酶激酶3b （GSK-3b）的特异性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药物来治疗双相情感障碍患者。此外，GSK-3酶的促凋亡特性表明这种抑制剂可能用作神经保护剂。神经保护可能进一步促进情绪障碍药物的治疗效果。目前有许多合成的GSK-3抑制剂可用，但其中许多还没有在一系列生物试验中得到充分表征，也不容易提供给学术研究人员。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，它们真正的激酶选择性谱和它们在体内的作用，包括可能的副作用，仍有待确定。显然，新型的、选择性的和安全的GSK-3抑制剂需要作为药物工具和治疗方法应用于各种中枢神经系统疾病，包括各种双相情感障碍，以及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效的GSK-3抑制剂，这些抑制剂来自于我们对staurosporine的SAR研究。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，进一步的研究努力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，进一步扩展和改进我们已经确定的有效GSK-3抑制剂；选择新的配体用于合成将有助于使用硅对接方法和这些化合物然后合成以毫克至克的量；AIM 2：所有新合成的配体将在激酶测定中进行测试，以评估其抑制GSK-3亚型（a和b）的选择性和效力。对于最佳化合物（Kj值< 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，以获得一定程度的激酶选择性；通过在细胞培养实验中检测其神经保护作用，进一步表征选择性配体的体外效应；AIM 3：检查最佳GSK-3抑制剂（Ki < 25 nM，对其他激酶的选择性至少为10倍，并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和抗躁狂作用的能力；这一目标将由我们在PsychoGenics Inc.的行为合作者使用他们的专利SmartCube技术来实现。

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.