Selective DAT Inhibitor for Treatment of ADHD

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