Opioids are powerful analgesics clinically used in treatment of chronic pain; they are also rewarding, and thus have high risk for abuse and dependence. Up to 25% of all patients receiving long-term opioid therapy struggle with opioid addiction, which is especially concerning considering that more than 191 million prescriptions for opioids were dispensed to patients in 2017 leading to the current opioid crisis. This has led to the search of novel strategies/therapeutic targets to treat pain. Hypothalamic neuropeptide receptors have emerged as potential targets for development of therapeutics for the treatment of substance use disorders. With the intent of identifying additional neuropeptide receptor systems, we recently deorphanized the hypothalamic receptor GPR83 as a receptor for an abundant neuropeptide, PEN. GPR83 is expressed in the reward centers of the brain. Also, local knock-down of GPR83 leads to attenuation of the rewarding effects of morphine making GPR83 a potential target for the development of novel therapeutics. The studies in this application are to characterize a recently identified small molecule antagonist targeting GPR83 with the intent of identifying drugs for the treatment of substance use disorders. These studies are highly significant since they are likely to open novel therapeutic possibilities for the treatment of addiction.
The studies in this application are to characterize a small molecule antagonist of GPR83, a receptor that is thought to play a critical role in regulating rewarding behaviors. Using a combination of molecular pharmacology, homology modeling, in silico docking, and medicinal chemistry we have identified a highly selective antagonist. The studies described here will characterize this molecule with regards to its ability to attenuate the rewarding effects of drugs of abuse and are likely to lead to the potential development of a therapeutic for the treatment of the disorders of the reward pathway including addiction.
