The opioid epidemic is one of the worst public health crises the United States has ever endured. This is exacerbated by the rising prevalence of concomitant stimulant use, a practice that has recently been shown to increase the toxicity of opioids. While there are treatment options for those with opioid use disorders, there are no FDA-approved therapeutics for either stimulant or polysubstance use disorders. It is hypothesized that opioid ligands acting as bifunctional kappa opioid receptor (KOR) agonists/mu opioid receptor (MOR) low-efficacy partial agonists will serve as effective medications to treat co-occurring opioid and stimulant use disorders. These compounds have the potential to decrease the “dopamine-high” caused by substances of abuse due to their function at the KOR, while simultaneously lacking any dysphoric side effects typical of a KOR agonist as a result of their MOR activity. Such characteristics may yield a novel polysubstance use disorder treatment with reduced abuse liability and increased treatment compliance compared to currently available opioid use disorder treatments. Thirty-two novel chemical entities designed towards such a pharmacological profile have been synthesized. The cellular and behavioral pharmacology of the synthesized compounds were then evaluated in a progressive, tier-wise manner. First, competitive radioligand binding assays were used to determine binding affinity and selectivity for the KOR, MOR, and delta opioid receptor (DOR). Then, [<sup>35</sup>S]GTP<i>γ</i>S binding assays were utilized to assess the efficacy and functional activity of ligands at the three opioid receptors. Third, identified hits were further tested for their opioid agonism using warm-water tail immersion assays in mice. Last, the most promising leads were characterized through self-administration assays to gauge their potencies at reducing polysubstance use in rats.

Development of KOR/MOR dual opioid agonists as a potential treatment for polysubstance use disorders

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ACS Fall 2022

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