2. Academic Validation
  3. Activity of Mitragyna speciosa ("Kratom") Alkaloids at Serotonin Receptors

Activity of Mitragyna speciosa ("Kratom") Alkaloids at Serotonin Receptors

  • J Med Chem. 2021 Sep 23;64(18):13510-13523. doi: 10.1021/acs.jmedchem.1c00726.
Francisco León 1 2,  Samuel Obeng 1 3,  Marco Mottinelli 1,  Yiming Chen 4,  Tamara I King 5 6,  Erin C Berthold 5 6,  Shyam H Kamble 5 6,  Luis F Restrepo 3,  Avi Patel 3,  Lea R Gamez-Jimenez 3,  Carolina Lopera-Londoño 1,  Takato Hiranita 3,  Abhisheak Sharma 5 6,  Aidan J Hampson 7,  Clinton E Canal 4,  Lance R McMahon 3,  Christopher R McCurdy 1 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
  • 2 Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States.
  • 3 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, Georgia 30341, United States.
  • 5 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
  • 6 Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, Florida 32610, United States.
  • 7 Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland 20892, United States.
PMID: 34467758 DOI: 10.1021/acs.jmedchem.1c00726
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.

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