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

Abstract

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 (MP). Although these three alkaloids have been shown to preferentially activate the G protein signaling pathway by binding and allosterically modulating the μ-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.

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

“…The crystal structure of active murine MOR bound to BU72 (PDB id: 5C1MF) was prepared for molecular docking of SC1, SC3, SC4, SC11, SC12, SC13, 11-F, morphine, and buprenorphine, using the protocol we recently reported in the literature for docking and simulations of kratom alkaloids, including mitragynine and 7OH mitragynine. 72 Molecular docking of morphine and buprenorphine was achieved by overlapping core heavy atoms onto the co-crystal compound BU72. In contrast, SC1, SC3, SC4, SC11, SC12, SC13, and 11-F were aligned onto mitragynine and 7OH mitragynine binding poses that had been previously obtained 72 mitragynine and mitragynine 38 were used here.…”

“…19 Metabolism of mitragynine to 7OH in vitro 24 and in dogs 25 has been reported by other groups too. More recently, we also reported an atomic-level description of how kratom alkaloids may bind and allosterically modulate MOR 21 . In vivo studies in mice revealed that kratom and a number of its alkaloids are analgesic 16,18,19,[26][27][28] ameliorate opioid physical dependence, 23,26 decrease alcohol intake 22 , and inhibit self-administration of heroin in rats.…”

“…[11][12][13][14][15][16] In recent years, we have become interested in the chemistry and pharmacology of kratom alkaloids as probes to understand opioid receptor function. 11,[17][18][19][20][21][22][23] Previous reports from our group reported that mitragynine (possessing an indole core), its oxidation product 7OH (possessing an indolenine core), and mitragynine pseudoindoxyl (MP, a skeletal rearrangement product of 7OH with a spiro-pseudoindoxyl core) (Figure 1A), are all opioid antinociceptive agents 18,19 and Gprotein biased MOR agonists. 17,18,20,22 We also reported oxidative metabolism of mitragynine to 7OH mitragynine using a CYP3A-mediated pathway following oral administration of mitragynine in mice.…”

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

“…Although kratom was reportedly used to substitute for opiate addiction and cure it (37), the demonstration of their binding by MsK had to await the discovery of opioid receptors (38,39). Mitragynine and other kratom alkaloids were shown to be possibly allosteric (40) agonists to opioid receptors (41)(42)(43)(44), to possess analgesic properties thanks to their binding to brain µand δ-opioid receptors, and to induce ileal and vas deferens distention through the same receptors at peripheral sites (43,45). These properties were long harnessed by traditional healers in the countries where kratom grows.…”

Ion-water coupling controls class A GPCR signal transduction pathways

“…To resolve their role in signalling, we applied Shannon’s mutual information (26, 28) and McGill’s interaction information (also called co-information) (29–32), as “State Specific Information” (SSI), in order to quantify information shared through coupled transitions of discrete residue and internal water states. In contrast to information theoretic approaches that analyze correlations in protein dynamics in cartesian space (most often C α motions) (6, 31, 33– 37), SSI derives from internal coordinate and state-based mutual information frameworks (38–41). It is therefore closely aligned with the concept of GPCR microswitches by requiring a change between at least two distinct conformational states for information exchange.…”