Kratom is an opioid-containing plant that is currently a federally unscheduled substance within the United States. Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that the mu opioid receptor (MOR) actions of kratom are dependent on the alkaloid mitragynine and its first-pass metabolite, 7-hydroxy mitragynine. Similarly, we have shown that a semi-synthetic derivative of 7-hydroxy mitragynine named mitragynine pseudoindoxyl shows mixed mu opioid-delta opioid actions. To continue investigations on kratom since there are atleast 54 known alkaloids present, we developed extraction and semi-synthetic methods to isolate and pharmacologically characterize five minor alkaloids. These minor alkaloids (corynantheidine, mitraciliatine, isopaynantheine, corynoxine and corynoxine B) differ in the stereochemistry at C3 and/or C20 from parent mitragynine scaffold. Mitraciliatine and a related alkaloid isopaynantheine (C20 vinyl analog) showed mixed mu opioid receptor/kappa opioid receptor (KOR) affinity and G-protein activity with differential βarrestin2 signaling profile. In addition, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl (SC11), methyl (SC12), 3’-furanyl (SC13), were characterized using in vitro assays. SC11-13 were partial agonists with lower efficacy than morphine in heterologous G-protein assays. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together characterization of natural products and semi-synthetics derived from kratom has led to novel probes for elucidating opioid actions in vivo as well as represent novel class of MOR modulators with functional selectivity in vivo.

Chemistry and pharmacology of kratom alkaloids

ACS Fall 2021

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