This study describes the development of a synthetic method to selectively functionalize the C11 position of the mitragynine (MG) scaffold, a key alkaloid found in the kratom plant. The researchers found that substitutions at the C11 position, particularly the introduction of a fluorine atom, can significantly reduce the signaling efficacy of the compound at the mu-opioid receptor (MOR). This is an important finding, as low-efficacy opioid agonists are of interest for the development of safer opioid medications with reduced adverse effects. The study used a combination of chemical synthesis, in vitro receptor assays, and in vivo mouse studies to explore the structure-activity relationships of these MG derivatives.
This study was conducted primarily in a laboratory setting, using synthetic chemistry techniques and in vitro/in vivo pharmacological assays. The experiments involved testing the compounds on mouse and human opioid receptors, as well as evaluating their analgesic effects in mice.
Key takeaways:
- The researchers developed a method to selectively functionalize the C11 position of the MG scaffold, a previously unexplored region.
- Substitutions at the C11 position, particularly fluorine, can dramatically reduce the signaling efficacy of these compounds at the MOR.
- The 11-fluoro-7-hydroxymitragynine compound exhibited low efficacy in both in vitro and in vivo assays, suggesting it may be a useful lead for the development of safer opioid therapeutics.
- This study highlights the importance of exploring structure-activity relationships of complex natural product scaffolds, like those found in kratom, to identify promising drug candidates.
For further reading:
Link: https://www.nature.com/articles/s41467-021-23736-2
Full Citation:
Bhowmik, S., Galeta, J., Havel, V., Nelson, M., Faouzi, A., Bechand, B., Ansonoff, M.,
Fiala, T., Hunkele, A., Kruegel, A. C., Pintar, J. E., Majumdar, S., Javitch, J. A., & Sames, D. (2021). Site
selective CH functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid
receptor signaling efficacy. Nature Communications, 12(1), 1-14.
