PD2005: A CNS active DAT inhibitor for improving cognitive deficits in traumatic

描述(由申请人提供)：目前SBIR第一阶段可行性研究的目的是评估我们的选择性多巴胺(DA)运输抑制剂PD2005在改善与创伤性脑损伤(TBI)相关的认知障碍方面的有效性。短时或工作记忆、处理速度和注意力等执行功能缺陷在脑外伤患者中普遍存在。由于就业生产率的下降，与脑损伤相关的认知缺陷给美国经济造成了约600亿美元的损失。神经创伤基金会工作组最近建立了治疗脑外伤后神经行为后遗症的循证治疗标准[40]。该小组建议使用哌醋甲酯(利他林(R))，它通过抑制DA转运体(DAT)促进DA激动化，以改善与脑损伤相关的认知障碍。然而，哌甲酸甲酯具有很大的滥用和成瘾潜力，并受到附表II的控制。因此，需要无滥用潜力的DA认知增强剂。申请组织的先导化合物PD2005是一种选择性的DAT抑制剂，作为先导化合物，它提高了认知能力，但没有滥用潜力。我们的先导化合物是苯并托品类似物。母分子苯妥拉平是FDA批准的选择性高亲和力DAT抑制剂，临床应用已有30多年。不幸的是，苯妥拉平是一种有效的抗胆碱能药物。对我们专有的苯并托品类似物库进行的广泛的先导优化研究导致了PD2005，它没有显示出抗胆碱能特性。与哌醋甲酯相比，PD2005在结合研究中显示出7倍的DAT抑制和10倍的纹状体[~3H]DA再摄取。外周给药时，铅化合物显著改善了注意力缺陷动物模型的工作记忆和持续注意力。最后，通过猴子和大鼠的自我给药研究，PD2005没有显示出滥用的可能性。总体而言，初步数据表明，我们的先导化合物缺乏滥用潜力，在改善与脑损伤相关的认知缺陷方面表现出强大的有效性。我们唯一的特定目标是：特定目标：在受控皮质撞击大鼠脑损伤模型中评估PD2005对工作记忆的影响。PD2005的S的疗效将与MPH和车辆治疗的对照组在不同的伤害严重程度(假的，轻度的，中度的和重度的脑外伤)进行比较。工作记忆将采用水T迷宫延迟不匹配放置任务进行评估。 公共卫生相关性：在目前的应用中，我们建议进行临床前研究，以评估我们的专利化合物PD2005-一种选择性的多巴胺转运体抑制剂-是否是改善创伤性脑损伤(TBI)后认知障碍的有效治疗方法。这些临床前研究将评估PD2005对轻度、中度或重度脑外伤后认知障碍的疗效。此外，还将评估阳性对照--哌醋甲酯--一种FDA批准的用于治疗脑外伤患者认知障碍的药物的效果。

DESCRIPTION (provided by applicant): The purpose of the present SBIR Phase 1 feasibility study is to assess the efficacy of our selective dopamine (DA) transport inhibitor PD2005 in improving cognitive deficits associated with traumatic brain injury (TBI). Executive function deficits like short term or working memory, processing speed, and attention are commonly prevalent in TBI patients. TBI-associated cognitive deficits cost the US economy about $ 60 BN due to losses in job productivity. The Neurotrauma Foundation Working Group recently established evidence- based treatment standards to treat neurobehavioral sequelae after TBI [40]. The Group recommended use of methylphenidate (Ritalin(R)), which promotes DA agonism by inhibiting DA transporter (DAT), to improve TBI-associated cognitive deficits. However, methylphenidate possesses substantial abuse and addiction potential and is subject to Schedule II controls. Thus, a need exists for DA cognitive enhancers without abuse potential. The applicant organization's lead compound PD2005 is a selective DAT inhibitor as lead compound, which enhances cognition but possesses no abuse potential. Our lead compound is a benztropine analog. The parent molecule benztropine is an FDA- approved selective high affinity DAT inhibitor in clinical use for over 30 years. Unfortunately, benztropine is a potent anticholinergic. Extensive lead optimization studies with our proprietary library of benztropine analogs led to PD2005 which demonstrated no anticholinergic properties. PD2005 demonstrated a 7- fold greater DAT inhibition in binding studies and 10- fold lower striatal [3H] DA reuptake compared to methylphenidate. The lead compound when administered peripherally significantly improved working memory and sustained attention in an animal model of attention deficit. Finally, PD2005 demonstrated no abuse potential as assessed by monkey and rat self-administration studies. Overall, the preliminary data suggest that our lead compound has a lack of abuse potential and can demonstrate robust efficacy in improving TBI-associated cognitive deficits. Our sole Specific Aim is: Specific Aim: Assess the effect of PD2005on Working Memory in a controlled cortical impact rat TBI model. PD2005's efficacy will compared with MPH and vehicle- treated controls across differing injury severity (sham, mild, moderate and severe TBI). Working Memory will be assessed employing the water T-maze Delayed Non-Match to Place task. PUBLIC HEALTH RELEVANCE: In the present application, we propose preclinical studies to assess whether our proprietary compound, PD2005 - a selective inhibitor of the dopamine transporter, is an effective treatment for improving cognitive deficits after traumatic brain injury (TBI). These preclinical studies will assess the efficacy of PD2005 on cognitive deficits following mild, moderate or severe TBI. Additionally, the effect of a positive control, methylphenidate - a FDA-approved drug used to treat cognitive deficits in TBI patients will be assessed.