Selective DAT Inhibitor for Treatment of ADHD

描述（由申请人提供）：目前，非选择性多巴胺（DA）转运抑制剂哌甲酯和d-安非他明是唯一被批准用于治疗注意缺陷/多动障碍（ADHD）的一线药物。由于这两种药物都是主要用于儿童的附表二滥用药物，国家药物滥用研究所和国家精神卫生研究所的一个优先事项是开发一种安全有效的替代品，以替代这些药物，很少或没有滥用的可能性。本研究的目的是评估我们的先导化合物PD2005是否符合这些标准。广泛的研究表明，这两种药物治疗ADHD的作用机制是抑制DA转运体。PD2005是一种选择性DA转运抑制剂。它是苯托品的类似物，苯托品是fda批准的选择性DA转运抑制剂，已在临床使用超过30年。不幸的是，苯妥品是一种有效的抗胆碱能药物，因此不能用于治疗多动症。广泛的铅优化研究已经确定苯托品类似物PD2005是一种没有抗胆碱能特性的选择性DA转运抑制剂。此外，PD2005是一种精神兴奋剂，在临床前研究中没有滥用的可能性（例如，不支持猴子自我给药）。本研究将评估PD2005在临床前ADHD筛查模型中的效果，我们的具体目标是：具体目标1：评估PD2005对ADHD啮齿动物多动模型中运动活动和运动活动昼夜节律模式的影响。具体目标2：评估PD2005对执行认知功能的影响，采用两种临床前ADHD啮齿动物模型：a)工作记忆和b)持续注意。在目前的申请中，我们提出临床前研究，以评估我们的专利化合物PD2005 -多巴胺转运体的选择性抑制剂，是否能有效治疗注意力缺陷/多动障碍（ADHD）。这些临床前研究将评估多动症在人类中观察到的三种主要症状：多动、工作记忆和持续注意力。PD2005对ADHD所有这三个方面的影响将在拟议的研究中确定。此外，阳性对照哌醋甲酯的效果将在所有研究中进行评估，哌醋甲酯是fda批准的治疗人类多动症的药物

DESCRIPTION (provided by applicant): Currently, the non-selective dopamine (DA) transport inhibitors methylphenidate and d- amphetamine are the only approved first line treatments for Attention Deficit/Hyperactivity Disorder (ADHD). As both drugs are Schedule II drugs of abuse primarily administered to children, a priority at the National Institute on Drug Abuse and the National Institute of Mental Health is to developed a safe and effective alternative to these drugs that has little or no abuse potential. The goal of the present studies is to assess whether our lead compound, PD2005, meets these criteria. Extensive research suggests that the mechanism of action of both drugs in treating ADHD is inhibition of the DA transporter. PD2005 is a selective DA transport inhibitor. It is an analog of benztropine, a FDA-approved selective DA transport inhibitor in clinical use for over 30 years. Unfortunately, benztropine is a potent anticholinergic that precluded it use as an ADHD treatment. Extensive lead optimization studies have identified the benztropine analog, PD2005, as a selective DA transport inhibitor with no anticholinergic properties. Further, PD2005 is a psychostimulant that demonstrates no abuse potential in preclinical studies (e.g. does not support self- administration in monkeys). The proposed studies will assess the efficacy of PD2005 in well established preclinical ADHD screening models, our Specific Aims are: Specific Aim 1: Assess the effect of PD2005 on locomotor activity in an ADHD rodent model of hyperactivity and on the circadian pattern of locomotor activity. Specific Aim 2: Assess the effect of PD2005 on executive cognitive function employing two preclinical ADHD rodent models of: a) working memory, and b) sustained attention. 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 Attention-Deficit/Hyperactivity Disorder (ADHD). These preclinical studies will assess three main symptoms of ADHD observed in humans, hyperactivity, working memory and sustained attention. The effect of PD2005 on all three of these dimensions of ADHD will be determined in the proposed studies. Additionally, the effect of a positive control, methylphenidate - a FDA-approved treatment for ADHD in humans, will be assessed in all studies