Open AccessActivity of Mitragyna speciosa (“Kratom”) Alkaloids at Serotonin Receptors
Author(s) -
Francisco León,
Samuel Obeng,
Marco Mottinelli,
Yiming Chen,
Tamara I. King,
Erin C. Berthold,
Shyam H. Kamble,
Luís Fernando Restrepo,
Avi Patel,
Lea R. Gamez-Jimenez,
Carolina Lopera-Londoño,
Takato Hiranita,
Abhisheak Sharma,
Aidan Hampson,
Clinton E. Canal,
Christopher R. McCurdy
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00726
Subject(s) - chemistry , alkaloid , pharmacology , serotonin , receptor , in vivo , opioid , in vitro , antagonist , biochemistry , stereochemistry , biology , microbiology and biotechnology
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-HT 1A Rs and 5-HT 2B Rs, unlike the principal kratom alkaloid mitragynine. Both alkaloids produced antinociceptive properties in rats via an opioid receptor-independent mechanism, and neither activated 5-HT 2B Rs in vitro. Paynantheine, speciogynine, and mitragynine induced lower lip retraction and antinociception in rats, effects blocked by a selective 5-HT 1A R antagonist. In vitro functional assays revealed that the in vivo 5-HT 1A R 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-HT 2B R, suggesting low inherent risk of causing valvulopathy. The 5-HT 1A R agonism by kratom alkaloids may contribute to the mood-enhancing effects associated with kratom use.