Kratom alkaloids have mostly been evaluated for their opioid activity but less at other targets that could contribute to their physiological effects. Here, we investigated the in vitro and in vivo activity of kratom alkaloids at serotonin receptors (5-HTRs). Paynantheine and speciogynine exhibited high affinity for 5-HTRs and 5-HTRs, unlike the principal kratom alkaloid mitragynine. Both alkaloids produced antinociceptive properties in rats via an opioid receptor-independent mechanism, and neither activated 5-HTRs in vitro. Paynantheine, speciogynine, and mitragynine induced lower lip retraction and antinociception in rats, effects blocked by a selective 5-HTR antagonist. In vitro functional assays revealed that the in vivo 5-HTR agonistic effects may be due to the metabolites 9--desmethylspeciogynine and 9--desmethylpaynantheine and not the parent compounds. Both metabolites did not activate 5-HTR, suggesting low inherent risk of causing valvulopathy. The 5-HTR agonism by kratom alkaloids may contribute to the mood-enhancing effects associated with kratom use.
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| http://dx.doi.org/10.1021/acs.jmedchem.1c00726 | DOI Listing |
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