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).
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. ? ? ?
