Development of a Potential Treatment for Polysubstance Use Disorders

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Project Summary The long-term objective of this proposed research is to develop a potent and selective kappa opioid receptor (KOR) agonist/mu opioid receptor (MOR) low-efficacy partial agonist as a potential treatment for polysubstance use disorders. Not only are the opioid epidemic and the misuse/abuse of stimulants both major health concerns on their own, but the two classes of drugs are often used concomitantly, resulting in polysubstance use disorders. More specifically, the use of opioids and stimulants in combination has been shown to increase neurotoxicity. The growing population of people suffering from these use disorders is under-served as there are currently no FDA-approved therapeutics for either stimulant use disorders or polysubstance use disorders. This makes the development of new treatment options imperative. Nalfurafine (NLF), a KOR agonist and MOR partial agonist clinically approved to treat uremic pruritis in Japan, has yielded intriguing pharmacological results; it is responsible for a decrease in both opioid and stimulant self-administration, doesn’t result in tolerance or self-administration when used in isolation, yields conditioned place aversion only at high doses, and importantly does not exhibit dysphoric effects. Despite these promising characteristics, NLF is not suitable for repurposing due to its low distribution in the central nervous system, though it may act as a lead for further exploration and development. Therefore, it is hypothesized that KOR agonist/MOR low-efficacy partial agonist dual ligands will serve as effective medications to treat comorbid opioid and stimulant use disorders; further, it is proposed that studying analogs of NLF will lead to the development of this treatment. In this scenario, a KOR agonist will function to attenuate the rewarding effects of opioids and stimulants discouraging abuse, while a MOR partial agonist will function to prevent any psychotomimetic effects typical of KOR agonists. This hypothesis will be tested in three specific aims. In Aim 1, analogs of NLF will be designed and synthesized. Aim 2 will then facilitate the in vitro testing of designed ligands and controls for binding affinity, selectivity, potency, efficacy, and functional activity. The most promising ligands identified from Aim 2 will be subjected to further testing for the determination of their pharmacodynamic profiles in Aim 3; this will include tests of in vivo functional activity, efficacy, potency, time-course and receptor mediation using warm-water tail immersion assays, as well as determination of behavioral effects via self-administration assays. Success of this program will further understanding of NLF structure-activity relationships and lead to the development of a novel ligand with potential as a treatment for polysubstance use disorders.