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

doi:10.1021/acs.jmedchem.1c00726

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 journal › Article › peer-review

36 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-HT_1ARs and 5-HT_2BRs, unlike the principal kratom alkaloid mitragynine. Both alkaloids produced antinociceptive properties in rats via an opioid receptor-independent mechanism, and neither activated 5-HT_2BRs in vitro. Paynantheine, speciogynine, and mitragynine induced lower lip retraction and antinociception in rats, effects blocked by a selective 5-HT_1AR antagonist. In vitro functional assays revealed that the in vivo 5-HT_1AR 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_2BR, suggesting low inherent risk of causing valvulopathy. The 5-HT_1AR agonism by kratom alkaloids may contribute to the mood-enhancing effects associated with kratom use.

Original language	English (US)
Pages (from-to)	13510-13523
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00726
State	Published - Sep 23 2021
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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León, F., Obeng, S., Mottinelli, M., Chen, Y., King, T. I., Berthold, E. C., Kamble, S. H., Restrepo, L. F., Patel, A., Gamez-Jimenez, L. R., Lopera-Londoño, C., Hiranita, T., Sharma, A., Hampson, A. J., Canal, C. E., McMahon, L. R., & McCurdy, C. R. (2021). Activity ofMitragyna speciosa(“Kratom”) Alkaloids at Serotonin Receptors. Journal of Medicinal Chemistry, 64(18), 13510-13523. https://doi.org/10.1021/acs.jmedchem.1c00726

León, F, Obeng, S, Mottinelli, M, Chen, Y, King, TI, Berthold, EC, Kamble, SH, Restrepo, LF, Patel, A, Gamez-Jimenez, LR, Lopera-Londoño, C, Hiranita, T, Sharma, A, Hampson, AJ, Canal, CE, McMahon, LR & McCurdy, CR 2021, 'Activity ofMitragyna speciosa(“Kratom”) Alkaloids at Serotonin Receptors', Journal of Medicinal Chemistry, vol. 64, no. 18, pp. 13510-13523. https://doi.org/10.1021/acs.jmedchem.1c00726

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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.",

author = "Francisco Le{\'o}n and Samuel Obeng and Marco Mottinelli and Yiming Chen and King, {Tamara I.} and Berthold, {Erin C.} and Kamble, {Shyam H.} and Restrepo, {Luis F.} and Avi Patel and Gamez-Jimenez, {Lea R.} and Carolina Lopera-Londo{\~n}o and Takato Hiranita and Abhisheak Sharma and Hampson, {Aidan J.} and Canal, {Clinton E.} and McMahon, {Lance R.} and McCurdy, {Christopher R.}",

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doi = "10.1021/acs.jmedchem.1c00726",

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AU - León, Francisco

AU - Obeng, Samuel

AU - Mottinelli, Marco

AU - Chen, Yiming

AU - King, Tamara I.

AU - Berthold, Erin C.

AU - Kamble, Shyam H.

AU - Restrepo, Luis F.

AU - Patel, Avi

AU - Gamez-Jimenez, Lea R.

AU - Lopera-Londoño, Carolina

AU - Hiranita, Takato

AU - Sharma, Abhisheak

AU - Hampson, Aidan J.

AU - Canal, Clinton E.

AU - McMahon, Lance R.

AU - McCurdy, Christopher R.

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N2 - 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.

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

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