Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β‑Arrestin‑2

Natural products
found in Mitragyna speciosa,
commonly known as kratom, represent diverse scaffolds (indole, indolenine,
and spiro pseudoindoxyl) with opioid activity, providing opportunities
to better understand opioid pharmacology. Herein, we report the pharmacology
and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl
(3), an oxidative rearrangement product of the corynanthe
alkaloid mitragynine. 3 and its corresponding corynantheidine
analogs show promise as potent analgesics with a mechanism of action
that includes mu opioid receptor agonism/delta opioid receptor antagonism.
In vitro, 3 and its analogs were potent agonists in [35S]­GTPγS assays at the mu opioid receptor but failed
to recruit β-arrestin-2, which is associated with opioid side
effects. Additionally, 3 developed analgesic tolerance
more slowly than morphine, showed limited physical dependence, respiratory
depression, constipation, and displayed no reward or aversion in CPP/CPA
assays, suggesting that analogs might represent a promising new generation
of novel pain relievers.