Opioid analgesics are the gold standard for treating chronic and severe pain. However, they are plagued with negative side effects, including tolerance, dependence, addiction, constipation, and death through respiratory depression. Millions of Americans are given prescription opioids to manage their pain, creating the need for strong opioid analgesics that are devoid of these side effects. A growing body of evidence suggests that agonism at the µ-opioid receptor (MOR) with concomitant antagonism at the δ-opioid receptor (DOR) can induce opioid mediated analgesia with reduced or abolished side effects. To this end, our lab has developed a bifunctional peptidomimetic series with the aforementioned profile that induces antinociception <i>in vivo</i> without tolerance, dependence, or drug-seeking behavior. However, these ligands express poor metabolic stability in mouse liver microsome assays. As such, we have opted to pursue an SAR campaign aimed at improving their pharmacokinetic profile. This SAR campaign has produced novel structures that are highly potent and efficacious MOR ligands, do not stimulate DOR, are stable in mouse liver microsomes, and show antinociception <i>in vivo</i>.

Structural evolution of novel opioid peptidomimetics with reduced abuse liabilities

2019 Spring National Meeting

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