Activity ofMitragyna speciosa(“Kratom”) Alkaloids at Serotonin Receptors

Francisco León, Samuel Obeng, Marco Mottinelli, Yiming Chen, Tamara I. King, Erin C. Berthold, Shyam H. Kamble, Luis F. Restrepo, Avi Patel, Lea R. Gamez-Jimenez, Carolina Lopera-Londoño, Takato Hiranita, Abhisheak Sharma, Aidan J. Hampson, Clinton E. Canal, Lance R. McMahon, Christopher R. McCurdy

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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-HT1ARs and 5-HT2BRs, unlike the principal kratom alkaloid mitragynine. Both alkaloids produced antinociceptive properties in rats via an opioid receptor-independent mechanism, and neither activated 5-HT2BRs in vitro. Paynantheine, speciogynine, and mitragynine induced lower lip retraction and antinociception in rats, effects blocked by a selective 5-HT1AR antagonist. In vitro functional assays revealed that the in vivo 5-HT1AR agonistic effects may be due to the metabolites 9-O-desmethylspeciogynine and 9-O-desmethylpaynantheine and not the parent compounds. Both metabolites did not activate 5-HT2BR, suggesting low inherent risk of causing valvulopathy. The 5-HT1AR agonism by kratom alkaloids may contribute to the mood-enhancing effects associated with kratom use.

Original languageEnglish (US)
Pages (from-to)13510-13523
Number of pages14
JournalJournal of Medicinal Chemistry
Volume64
Issue number18
DOIs
StatePublished - Sep 23 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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