Probing the Activity of Mitragyna Speciosa (Kratom) Alkaloids at Serotonin G Protein‐Coupled Receptors

Abstract

The nation’s persistent opioid epidemic requires innovative treatment interventions. Mitragyna speciosa, or kratom, is an alkaloid‐containing tropical plant that has emerged as a potential opioid substitute therapy in recent decades. There are, however, no FDA‐approved uses for kratom, and scientists are actively engaged to elucidate the potential therapeutic benefits and harmful effects of kratom. Studies of kratom alkaloids have mainly focused on their opioid receptor activity, but emerging data show kratom has physiologically‐relevant activity at other biological targets. We recently reported that two kratom alkaloids prevalent in leaves of the kratom plant, speciogynine and paynantheine, bind to serotonin (5‐HT) 5‐HT1ARs and 5‐HT2BRs with affinities (Ki) less ≤100 nM and that their 9‐O‐desmethyl metabolites are efficacious agonists at 5‐HT1ARs (León et al., 2021 PMID: 34467758). We are undertaking studies to evaluate the pharmacology of the most prevalent alkaloids found in kratom leaves at each of the genetically‐encoded 5‐HT G protein‐coupled receptors (GPCRs). To further elucidate 5‐HTR G‐protein transduction pathways modulated by kratom alkaloids, we are utilizing the TRUPATH biosensor platform. By evaluating the potency and efficacy of kratom alkaloids to modulate the activity of unique G alpha subtypes linked to 5‐HTRs, we will provide fundamental 5‐HTR pharmacological characteristics of kratom alkaloids. The 5‐HT2BR is a crucial target for drug safety profiling since activation of this receptor can lead to cardiac valvulopathy. In addition, we are testing kratom alkaloids with an appreciable 5‐HT2BR affinity for their potential mitogenic activity in HEK cells utilizing [3H]thymidine incorporation. This research will provide crucial information about kratom’s pharmacological profile, independent of opioid receptors, that may contribute to its physiological effects.