Pharmacological Characterization of Synthetic Kratom Alkaloids for Improved Alcohol Use Disorder Therapeutics

Abstract

Background Kratom is an opioid-containing plant and currently a federally unscheduled substance within the U.S. that is used to self-medicate chronic pain and opioid dependence, serving as a substitute for illicit and prescription opioids. Similarly, some individuals with Alcohol Use Disorder (AUD) find kratom helpful in reducing AUD dependence and withdrawal symptoms. We have previously shown that the kratom alkaloids can dose-dependently decrease alcohol consumption in mice, and that this activity is dependent on delta opioid receptor (DOR) expression. However, the most potent of the alkaloids 7-OH mitragynine, exhibited rewarding properties, presumably due to its mu opioid receptor (MOR) pharmacology. We hypothesized that reduction of MOR potency relative to potency at DOR would lead to an improved therapeutic window with respect to reward liability and alcohol consumption. Methods A series of kratom analogs were pharmacologically characterized for their ability to bind to opioid receptors and elicit G-protein and beta-arrestin signaling using radioligand binding and cellular signaling assays. Using the 2-bottle choice assay of 10% alcohol consumption, wildtype and DOR knockout (DOR KO) mice were used to assess to what degree the kratom alkaloids could reduce alcohol use, and whether any effects were DOR-mediated. Drug reward was also assessed through conditioned place preference experiments. Results Kratom analogs are G-protein-biased at the opioid receptors, similar to their parent compounds. Kratom analog #2 showed the most favorable pharmacology with similar DOR potency but greatly reduced MOR potency compared to 7-OH mitragynine, and was capable of significantly decreasing ethanol consumption in wildtype mice at a dose of 10 mg/kg. CPP experiments and experiments with DOR KO mice are currently being completed for kratom analog #2 and will be useful in confirming DOR-mediated effects and whether the improved pharmacological profile of the analogs confers therapeutic benefits. Discussion Our results indicate that the development of potent, DOR-selective opioids could provide a pathway to treat alcohol use without being significantly rewarding, and that the kratom alkaloids provide useful scaffolds to jumpstart these efforts.