A functionally selective ghrelin receptor (GHSR) ligand for treatment of chemical and food addiction

Unmet Need

The number of Americans with addiction-related disorders, including substance use disorders (SUD) and food addiction is increasing rapidly each year. Recent estimates indicate that >20 million people in the U.S. have been diagnosed with an SUD and that 12-20% of individuals with obesity (>40% of the total population) meet diagnostic criteria for food addiction. The etiology of both chemical and food addiction is rooted in common neurobiology involving the 'reward' neurotransmitter dopamine. Accordingly, many appetite-regulating hormones are potent modulators of brain dopamine and strongly influence addictive behavior. The key appetite-stimulating hormone is ghrelin, which exerts its stimulatory effects on feeding and brain dopamine through its G protein-coupled receptor (GPCR) target — the ghrelin receptor GHSR. Unsurprisingly, most ghrelin-directed therapies to treat SUD or food addiction have attempted to completely block (antagonize) GHSR activity, but this often leads to problematic side effects, including anorexia, weight/ muscle/ bone loss, glucose dysregulation, and elevated blood pressure. Thus, there is a need for new treatment strategies that selectively modulate GHSR pathways to prevent these undesirable side effects while retaining anti-addictive potential.

Technology

Duke inventors have developed a small-molecule therapeutic candidate for the treatment of SUD and/or eating disorders such as food addiction. By selectively 'biasing' GHSR signaling, this novel compound is intended to improve anti-addictive efficacy while minimizes deleterious side effects. One GHSR signaling pathway through G proteins critically regulates endocrine and metabolic function; whereas, an alternate pathway through β-arrestin reinforces dopamine-dependent neuroplasticity and addictive behavior. Functionally selective (aka 'biased') ligands can be contrasted with current and past therapeutic candidates that activate/inhibit both pathways equally and thereby, often cause serious side effects or toxicity. This GHSR-selective, brain-penetrant therapeutic acts as a biased agonist towards the G protein pathway and diminishes β-arrestin-dependent cellular and behavioral effects. Thus, it allows normal endocrine/metabolic processes to occur while simultaneously curtailing dopamine-dependent reward. These advantageous characteristics have been demonstrated in vitro and in vivo using mouse models.

Other Applications

This technology can be used to treat a variety of conditions involving imbalances in brain dopamine and/or neurodegenerative disease. For example, its unique mechanism also makes it a promising therapeutic candidate for eating disorders (anorexia/cachexia, binge-eating disorder), alcohol use disorder, diabetes, Parkinson’s disease, Alzheimer's disease, and/or muscular atrophy, among others.

Advantages

• Selective and brain permeating GHSR ligand with a novel mechanism-of-action.
• Potentially fewer side effects than past or current ghrelin/GHSR therapeutics through biased activation of G protein signaling over the β-arrestin pathway.
• Wide range of potential indication areas, including addictions, eating disorders, and neurodegenerative diseases.