Selective DAT Inhibitor for Treatment of ADHD

描述(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-苯丙胺是唯一被批准的治疗注意力缺陷/多动障碍(ADHD)的一线药物。由于这两种药物都是主要给儿童使用的附表二滥用药物，国家药物滥用研究所和国家精神卫生研究所的优先事项是开发一种安全有效的替代药物，几乎没有滥用潜力。本研究的目标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是一种选择性的DA转运抑制剂。它是苯妥拉平的类似物，苯妥拉平是FDA批准的一种选择性DA转运抑制剂，临床使用超过30年。不幸的是，苯妥拉平是一种有效的抗胆碱能药物，这使得它无法用于治疗ADHD。广泛的先导优化研究已经确定苯妥拉平类似物PD2005是一种选择性的DA转运抑制剂，没有抗胆碱能特性。此外，PD2005是一种精神刺激剂，在临床前研究中没有滥用潜力(例如，不支持猴子的自我给药)。建议的研究将评估PD2005在已建立的临床前ADHD筛查模型中的有效性，我们的具体目标是：具体目标1：评估PD2005对ADHD多动啮齿动物模型中运动活动的影响以及对运动活动的昼夜节律的影响。具体目标2：使用两种临床前ADHD啮齿动物模型评估PD2005对执行认知功能的影响：a)工作记忆，b)持续注意。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--是否对注意力缺陷/多动障碍(ADHD)有效。这些临床前研究将评估在人类中观察到的ADHD的三个主要症状，即多动、工作记忆和持续注意力。PD2005对ADHD的这三个维度的影响将在拟议的研究中确定。此外，FDA批准的治疗人类多动症的阳性对照药物哌醋甲酯的效果将在所有研究中进行评估

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