Predicted Mode of Binding to and Allosteric Modulation of the μ-Opioid Receptor by Kratom's Alkaloids with Reported Antinociception In Vivo

Pain management devoid of serious opioid adverse effects is still far from reach despite vigorous research and development efforts. Alternatives to classical opioids have been sought for years, and mounting reports of individuals finding pain relief with kratom have recently intensified research on this natural product. Although the composition of kratom is complex, the pharmacological characterization of its most abundant alkaloids has drawn attention to three molecules in particular, owing to their demonstrated antinociceptive activity and limited side effects in vivo. These three molecules are mitragynine (MG), its oxidized active metabolite, 7-hydroxymitragynine (7OH), and the indole-to-spiropseudoindoxy rearrangement product of MG known as mitragynine pseudoindoxyl (NIP). Although these three alkaloids have been shown to preferentially activate the G protein signaling pathway by binding and allosterically modulating the mu-opioid receptor (MOP), a molecular level understanding of this process is lacking and yet important for the design of improved therapeutics. The molecular dynamics study and experimental validation reported here provide an atomic level description of how MG, 7OH, and MP bind and allosterically modulate the MOP, which can eventually guide structure-based drug design of improved therapeutics.

Automated summary

Research on kratom, a natural alternative for pain management, has intensified due to mounting reports of individuals finding pain relief with this product. Three alkaloids found in kratom, mitragynine, 7-hydroxymitragynine, and mitragynine pseudoindoxyl, have shown potential for pain relief with limited side effects. These alkaloids have been shown to selectively activate the G protein signaling pathway by binding and modulating the mu-opioid receptor, providing insight for the design of improved therapeutics.