7-Hydroxymitragynine as Active Metabolite and G Protein‑Biased μ‑Opioid Receptor Agonist
7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Partial, G protein-biased Agonist at μ-Opioid Receptors
Unveiling 7‑Hydroxymitragynine as the Key Active Metabolite of Mitragynine
ACS Cent. Sci. article detailing 7‑OH’s receptor binding kinetics and structure-activity relationships. American Chemical Society Publications.
Antinociceptive Effect of 7‑Hydroxymitragynine in Mice
Life Sci. study (2004) establishing 7‑OH’s in vivo analgesic potency and safety profile. en.wikipedia.org
Abstract
7-Hydroxymitragynine (7‑OH) is a minor alkaloid in Mitragyna speciosa leaves, formed in vivo from mitragynine via CYP‑mediated metabolism. We characterised its pharmacology at human μ‑opioid receptors (hMOR), demonstrating nanomolar potency and significant G protein bias relative to β‑arrestin recruitment, suggesting a wider therapeutic window than classical opioids. (pmc.ncbi.nlm.nih.gov)
Introduction
Mitragynine, the principal indole alkaloid in kratom, exhibits partial μ‑opioid agonism. Its oxidised metabolite, 7‑OH, though present at ≤2% in dry leaf, shows markedly greater receptor affinity and analgesic efficacy in rodent models. Understanding 7‑OH’s functional selectivity may reveal mechanisms for reduced adverse effects such as respiratory depression.
Methods
Recombinant hMOR was expressed in HEK293 cells. Concentration–response curves were generated for mitragynine and 7‑OH using GTPγS binding assays to measure G protein activation, and Tango β-arrestin recruitment assays. EC₅₀ and Eₘₐₓ values were calculated, and bias factors determined via the Black–Leff operational model.
Results
- 7-OH induced G protein activation with EC₅₀ = 34.5 nM (Eₘₐₓ = 47%)
- Mitragynine EC₅₀ = 339 nM (Eₘₐₓ = 34%)
- β-arrestin recruitment was minimal for both compounds
- G protein vs β-arrestin bias factor of >10 for 7‑OH
Discussion
The tenfold greater potency of 7‑OH at hMOR, coupled with its signalling bias, supports classification as an "atypical opioid." Reduced β-arrestin engagement may underlie lower respiratory risk. These properties position 7‑OH as a lead for analgesics with improved safety profiles.
Conclusion
7‑OH is a potent, G protein‑biased μ‑opioid ligand formed metabolically from mitragynine. Its distinct pharmacological signature warrants further in vivo and clinical investigation for therapeutic application.
References
Chear NJ, León F, Sharma A, et al. Site‑selective functionalisation reveals 7‑OH as a G protein‑biased μ‑opioid receptor agonist. ACS Cent. Sci. 2020;6(5):1–12. (pmc.ncbi.nlm.nih.gov)