Selective DAT Inhbitor for the Treatment of Obesity

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DESCRIPTION (provided by applicant): The purpose of the present SBIR Phase 1 feasibility study is to assess the efficacy of our selective dopamine transport (DAT) inhibitor, PD2007, for the treatment of obesity. The non-selective DAT inhibitor, d-amphetamine, is a potent anti-obesity treatment in humans. However, d- amphetamine, is not clinically approved for the treatment of obesity due primarily to its significant abuse and addiction potential. Preliminary Studies indicate that our benztropine analog, PD2007, is as effective as d-amphetamine at decreasing food intake. Preliminary Studies also indicate that PD2007 demonstrates no abuse potential in preclinical studies. That is, PD2007 does not support self- administered in monkeys. The long term goal of the proposed studies is to develop a safe and effective anti-obesity treatment with little or no abuse potential. Extensive research suggests that DAT inhibition is the anti-obesity mechanism of action of d- amphetamine. Benztropine is a selective high affinity DAT inhibitor that is safe and effective and in clinical use for over 30 years. Benztropine demonstrates no significant abuse potential and is a non- Scheduled drug. Unfortunately, benztropine is a potent anticholinergic which precludes it use as an anti-obesity treatment. Extensive lead optimization studies have identified the benzotropine analog, PD2007, as a selective DAT inhibitor with no anticholinergic properties and with no abuse potential in preclinical studies. The purpose of the proposed Specific Aims is to assess PD2007's effect on food intake, body weight and body fat in a well established preclinical model of obesity (high fat diet-induced obesity), as well as, to determine PD2007's effect on obesity related co-morbidities. Specific Aim 1: Determine the effect of PD2007 on food intake, body weight, energy expenditure, circadian activity levels and regional body fat/lean body mass in high-fat diet- induce obesity rats and standard lab chow diet rats. Specific Aim 2: Determine the effects of PD2007 on obesity-related co-morbidities in Specific Aim 1 animals (triglycerides, cholesterol, leptin, insulin and inflammatory cytokines levels, as well as, glucose tolerance and insulin-sensitivity). PUBLIC HEALTH RELEVANCE: In the present application, we propose preclinical studies to assess whether our proprietary compound, PD2007-a selective inhibitor of the dopamine transporter, is an effective treatment for obesity. These preclinical studies will assess the effect of varying doses of PD2007 on obesity induced by a high fat diet in rats as well as in rats fed a standard lab chow diet. Rats, like humans, when fed a diet rich in fats increase their food intake and become obese. The ability of PD2007 to decrease food intake, decrease body fat and to reverse obesity related co-morbidities such as insulin resistance and glucose intolerance will be determined in both groups of animals.