Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom

Abstract

Dry leaves of kratom (mitragyna speciosa) are anecdotally consumed as pain relievers and antidotes against opioid withdrawal and alcohol use disorders. There are at least 54 alkaloids in kratom; however, investigations to date have focused around mitragynine, 7-hydroxy mitragynine (7OH), and mitragynine pseudoindoxyl (MP). Herein, we probe a few minor indole and oxindole based alkaloids, reporting the receptor affinity, Gprotein activity, and βarrestin-2 signaling of corynantheidine, corynoxine, corynoxine B, mitraciliatine, and isopaynantheine at mouse and human opioid receptors. We identify corynantheidine as a mu opioid receptor (MOR) partial agonist, whereas its oxindole derivative corynoxine was an MOR full agonist. Similarly, another alkaloid mitraciliatine was found to be an MOR partial agonist, while isopaynantheine was a KOR agonist which showed reduced βarrestin-2 recruitment. Corynantheidine, corynoxine, and mitraciliatine showed MOR dependent antinociception in mice, but mitraciliatine and corynoxine displayed attenuated respiratory depression and hyperlocomotion compared to the prototypic MOR agonist morphine in vivo when administered supraspinally. Isopaynantheine on the other hand was identified as the first kratom derived KOR agonist in vivo. While these minor alkaloids are unlikely to play the majority role in the biological actions of kratom, they represent excellent starting points for further diversification as well as distinct efficacy and signaling profiles with which to probe opioid actions in vivo.

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

“…Over the past decade, kratom has been reported as a source for naturally occurring, G-protein–biased opioidergic alkaloids, and has been investigated for its effects on pain management ( Matsumoto et al, 2004 ; Kruegel et al, 2019 ; Chakraborty et al, 2021b ; Chakraborty and Majumdar, 2021 ), opioid withdrawal ( Wilson et al, 2020 , 2021 ), and alcohol abuse ( Gutridge et al, 2020 ) as well as its decreased reward profile relative to traditional opioids ( Hemby et al, 2019 ; Wilson et al, 2021 ). Here, we further probed the effects of kratom alkaloids and synthetic kratom alkaloid derivatives to obtain a better understanding of its in vivo pharmacology and in search of novel treatment options for alcohol use disorder.…”

Kratom (Mitragyna speciosa) Validation: Quantitative Analysis of Indole and Oxindole Alkaloids Reveals Chemotypes of Plants and Products

“…Recent literature is beginning to evaluate the pharmacological importance of the other major and minor alkaloids present in M. speciosa [15][16][17][18]. Investigation of the opioid and adrenergic binding affinities of five kratom alkaloids, including 2, 12, speciociliatine (15), corynantheidine, and 9-hydroxycorynantheidine, revealed that 15 exhibited stronger binding affinity to κand μopioid receptors than 12 [19]; interestingly, 12 and 15 only differ by their configuration at position C-3 [14].…”

The Chemical and Pharmacological Properties of Mitragynine and Its Diastereomers: An Insight Review

“…Meanwhile, absolute stereochemistry is found to be crucial in agonistic activity in the opioid receptor. In a recent report by Chakraborty et al (2021b) on the opioid receptor function of mitraciliatine (4), pharmacological evidence was reported on this phytoalkaloid. In this study, mitraciliatine (4) (K i (MOR): 135.1 ± 7.7 nM) portrayed partial opioid agonism and identified it as structurally unique natural products with safer, MOR-dependent antinociception.…”