Dr. Pushkar Kulkarni Receives the 2012 Davis Foundation Postdoctoral Fellowship Program in Eating Disorders Research
Dr. Pushkar Kulkarni, a Post-doctoral Associate working in the laboratory of Assistant Professor Ganesh Thakur, in the Department of Pharmaceutical Sciences received the 2012 Davis Foundation Fellowship in the amount of $153,000 over three years. Dr. Kulkarni’s project entitled “Positive Allosteric Modulators of CB1 Cannabinoid Receptor for the Treatment of Anorexia Nervosa” focuses on development of novel therapeutic agents for the treatment of anorexia nervosa.
Anorexia nervosa (AN) is potentially life-threatening psychiatric disorder characterized by abnormal eating behavior, self-induced weight loss, anhedonia, cognitive distortions about body shape and weight. Pharmacotherapeutic interventions for its treatment are limited to atypical antipsychotics and antidepressants. However, limited evidence of clinical benefits has kept them from being considered in routine care of AN patients.
The endocannabinoid system (ECS) has been recognized as an important target in reward processing, feeding behavior and CB1 receptors play critical role in several emotional and cognitive impairments. Studies in AN patients have linked related behavior disorders to a dysfunctional ECS. In recently concluded studies, Marinol® (THC) a CB1 agonist has been shown to attenuate weight loss in a rodent model of AN. Currently it is undergoing phase-III clinical trial for treatment of AN. However, use of THC or other CB1 direct-acting agonists is associated with undesirable CNS side effects, strong abuse potential and addiction. Accomplishing CB1 agonism through a different pharmacological mechanism represents a safer alternative.
One promising alternative approach is the development of positive allosteric modulators (PAMs) of CB1 which, by binding to a topographically distinct (allosteric) site from the orthosteric site, potentiate the action of endocannabinoids and selectively tune CB1 signaling pathway. As demonstrated with other GPCRs, this approach provides therapeutic gain with minimal adverse effects. This project aims to develop potent CB1 PAMs with improved physicochemical properties for initial use as in vitro and in vivo tools to study effect of such modulation in animal models of anorexia.