The endocannabinoid system (ECS) comprising of two cannabinoid receptors (CB1 and CB2), endogenous cannabinoids (eCB), enzymatic machinery in-charge of eCB synthesis and inactivation has been recognized as one of the most important modulatory system in the brain. It is known to impact neurobiology of reward processing and feeding behavior. ECS is underactive in individuals with anorexia nervosa (AN) leading to compensatory chronic upregulation of CB1 in cortical and subcortical brain areas. Moreover, an increase in plasma levels of anandamide, an endogenous CB1 agonist, has also been shown in these individuals.?9-Tetrahydrocannabinol (THC), a psychoactive component of marijuana and a CB1 agonist, is known to increase food intake and improve hedonic properties of food. Recently, THC has been shown to attenuate weight loss in a rodent model of AN. Currently THC is in phase-III clinical trial for the treatment of AN. However, THC or other CB1 direct-acting agonists are associated with undesirable CNS side effects, strong abuse and addiction potential which limit their use as medications. Accomplishing CB1 agonism through a different pharmacological mechanism such as positive allosteric modulation may provide a safer alternative. Our novel approach involves use of positive allosteric modulators (PAMs) for the treatment of AN. PAMs bind to a topographically distinct (allosteric) CB1 site, positively modulate the eCB signaling. We have synthesized a novel series of CB1 PAMs and evaluated their potential in-vitro and in-vivo. In functional assays (cAMP and b-arrestin) PAMs show a potentiation of agonist response. In our microdialysis studies PAMs showed negligible rise in dopamine level in nucleus accumbens shell, thus, indicating less abuse liability. In activity based anorexia model one of the PAMs showed a decrease in hyperactivity. Therefore, PAMs alone or in combination with lower doses of THC/CB1 agonist would maintain an acceptable therapeutic value in the treatment of AN.

Novel positive allosteric modulators of CB1 cannabinoid receptor for the treatment of anorexia nervosa

246th National Meeting (2013)

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