Activity of Mitragyna speciosa (“Kratom”) Alkaloids at Serotonin Receptors
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 h...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-09, Vol.64 (18), p.13510-13523 |
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| container_title | Journal of medicinal chemistry |
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| creator | León, Francisco Obeng, Samuel Mottinelli, Marco Chen, Yiming King, Tamara I Berthold, Erin C Kamble, Shyam H Restrepo, Luis F Patel, Avi Gamez-Jimenez, Lea R Lopera-Londoño, Carolina Hiranita, Takato Sharma, Abhisheak Hampson, Aidan J Canal, Clinton E McMahon, Lance R McCurdy, Christopher R |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.1c00726 |
| format | Article |
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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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c00726</identifier><identifier>PMID: 34467758</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Analgesics - therapeutic use ; Animals ; Behavior, Animal - drug effects ; Female ; HEK293 Cells ; Humans ; Male ; Nociceptive Pain - drug therapy ; Nociceptive Pain - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin - metabolism ; Secologanin Tryptamine Alkaloids - therapeutic use</subject><ispartof>Journal of medicinal chemistry, 2021-09, Vol.64 (18), p.13510-13523</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a445t-ae20c4106f387d5ab0743f76a3cbf50a25411a679a407e1d25df486f691de25a3</citedby><cites>FETCH-LOGICAL-a445t-ae20c4106f387d5ab0743f76a3cbf50a25411a679a407e1d25df486f691de25a3</cites><orcidid>0000-0003-2868-8073 ; 0000-0002-5064-2381 ; 0000-0002-7940-933X ; 0000-0002-9644-0750 ; 0000-0001-8695-2915 ; 0000-0001-5725-0439 ; 0000-0002-1664-1692 ; 0000-0003-0553-4039 ; 0000-0003-0360-6318</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c00726$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00726$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34467758$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>León, Francisco</creatorcontrib><creatorcontrib>Obeng, Samuel</creatorcontrib><creatorcontrib>Mottinelli, Marco</creatorcontrib><creatorcontrib>Chen, Yiming</creatorcontrib><creatorcontrib>King, Tamara I</creatorcontrib><creatorcontrib>Berthold, Erin C</creatorcontrib><creatorcontrib>Kamble, Shyam H</creatorcontrib><creatorcontrib>Restrepo, Luis F</creatorcontrib><creatorcontrib>Patel, Avi</creatorcontrib><creatorcontrib>Gamez-Jimenez, Lea R</creatorcontrib><creatorcontrib>Lopera-Londoño, Carolina</creatorcontrib><creatorcontrib>Hiranita, Takato</creatorcontrib><creatorcontrib>Sharma, Abhisheak</creatorcontrib><creatorcontrib>Hampson, Aidan J</creatorcontrib><creatorcontrib>Canal, Clinton E</creatorcontrib><creatorcontrib>McMahon, Lance R</creatorcontrib><creatorcontrib>McCurdy, Christopher R</creatorcontrib><title>Activity of Mitragyna speciosa (“Kratom”) Alkaloids at Serotonin Receptors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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.</description><subject>Analgesics - therapeutic use</subject><subject>Animals</subject><subject>Behavior, Animal - drug effects</subject><subject>Female</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Male</subject><subject>Nociceptive Pain - drug therapy</subject><subject>Nociceptive Pain - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Secologanin Tryptamine Alkaloids - therapeutic use</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1OG0EQhVsIBI7DDRCaJSzGqf6d8QbJQiFBGJBIsm6Ve3qgYWba6W4jecdBksv5JBlig2DDqhb13qvS9wg5oDCiwOgXNHF039rK3Nl2RA1AwdQWGVDJIBcliG0yAGAsZ4rxPfIpxnsA4JTxXbLHhVBFIcsBuZqY5B5dWma-zi5dCni77DCLc2ucj5gdrZ7-XARMvl09_T3OJs0DNt5VMcOU_bDBJ9-5Lruxxs6TD_Ez2amxiXZ_M4fk19nXn6ff8-n1t_PTyTRHIWTK0TIwgoKqeVlUEmdQCF4XCrmZ1RKQSUEpqmKMAgpLKyarWpSqVmNaWSaRD8nJOne-mD0zsF3_eaPnwbUYltqj0-83nbvTt_5RjxmXvCcyJEebgOB_L2xMunXR2KbBzvpF1EyqkkneA-ylYi01wccYbP16hoJ-rkL3VeiXKvSmit52-PbFV9ML-14Aa8F_u1-Erif2ceY_g02bZg</recordid><startdate>20210923</startdate><enddate>20210923</enddate><creator>León, Francisco</creator><creator>Obeng, Samuel</creator><creator>Mottinelli, Marco</creator><creator>Chen, Yiming</creator><creator>King, Tamara I</creator><creator>Berthold, Erin C</creator><creator>Kamble, Shyam H</creator><creator>Restrepo, Luis F</creator><creator>Patel, Avi</creator><creator>Gamez-Jimenez, Lea R</creator><creator>Lopera-Londoño, Carolina</creator><creator>Hiranita, Takato</creator><creator>Sharma, Abhisheak</creator><creator>Hampson, Aidan J</creator><creator>Canal, Clinton E</creator><creator>McMahon, Lance R</creator><creator>McCurdy, Christopher R</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2868-8073</orcidid><orcidid>https://orcid.org/0000-0002-5064-2381</orcidid><orcidid>https://orcid.org/0000-0002-7940-933X</orcidid><orcidid>https://orcid.org/0000-0002-9644-0750</orcidid><orcidid>https://orcid.org/0000-0001-8695-2915</orcidid><orcidid>https://orcid.org/0000-0001-5725-0439</orcidid><orcidid>https://orcid.org/0000-0002-1664-1692</orcidid><orcidid>https://orcid.org/0000-0003-0553-4039</orcidid><orcidid>https://orcid.org/0000-0003-0360-6318</orcidid></search><sort><creationdate>20210923</creationdate><title>Activity of Mitragyna speciosa (“Kratom”) Alkaloids at Serotonin Receptors</title><author>León, Francisco ; Obeng, Samuel ; Mottinelli, Marco ; Chen, Yiming ; King, Tamara I ; Berthold, Erin C ; Kamble, Shyam H ; Restrepo, Luis F ; Patel, Avi ; Gamez-Jimenez, Lea R ; Lopera-Londoño, Carolina ; Hiranita, Takato ; Sharma, Abhisheak ; Hampson, Aidan J ; Canal, Clinton E ; McMahon, Lance R ; McCurdy, Christopher R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a445t-ae20c4106f387d5ab0743f76a3cbf50a25411a679a407e1d25df486f691de25a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Analgesics - therapeutic use</topic><topic>Animals</topic><topic>Behavior, Animal - drug effects</topic><topic>Female</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Male</topic><topic>Nociceptive Pain - drug therapy</topic><topic>Nociceptive Pain - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Secologanin Tryptamine Alkaloids - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>León, Francisco</creatorcontrib><creatorcontrib>Obeng, Samuel</creatorcontrib><creatorcontrib>Mottinelli, Marco</creatorcontrib><creatorcontrib>Chen, Yiming</creatorcontrib><creatorcontrib>King, Tamara I</creatorcontrib><creatorcontrib>Berthold, Erin C</creatorcontrib><creatorcontrib>Kamble, Shyam H</creatorcontrib><creatorcontrib>Restrepo, Luis F</creatorcontrib><creatorcontrib>Patel, Avi</creatorcontrib><creatorcontrib>Gamez-Jimenez, Lea R</creatorcontrib><creatorcontrib>Lopera-Londoño, Carolina</creatorcontrib><creatorcontrib>Hiranita, Takato</creatorcontrib><creatorcontrib>Sharma, Abhisheak</creatorcontrib><creatorcontrib>Hampson, Aidan J</creatorcontrib><creatorcontrib>Canal, Clinton E</creatorcontrib><creatorcontrib>McMahon, Lance R</creatorcontrib><creatorcontrib>McCurdy, Christopher R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>León, Francisco</au><au>Obeng, Samuel</au><au>Mottinelli, Marco</au><au>Chen, Yiming</au><au>King, Tamara I</au><au>Berthold, Erin C</au><au>Kamble, Shyam H</au><au>Restrepo, Luis F</au><au>Patel, Avi</au><au>Gamez-Jimenez, Lea R</au><au>Lopera-Londoño, Carolina</au><au>Hiranita, Takato</au><au>Sharma, Abhisheak</au><au>Hampson, Aidan J</au><au>Canal, Clinton E</au><au>McMahon, Lance R</au><au>McCurdy, Christopher R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activity of Mitragyna speciosa (“Kratom”) Alkaloids at Serotonin Receptors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2021-09-23</date><risdate>2021</risdate><volume>64</volume><issue>18</issue><spage>13510</spage><epage>13523</epage><pages>13510-13523</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34467758</pmid><doi>10.1021/acs.jmedchem.1c00726</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-2868-8073</orcidid><orcidid>https://orcid.org/0000-0002-5064-2381</orcidid><orcidid>https://orcid.org/0000-0002-7940-933X</orcidid><orcidid>https://orcid.org/0000-0002-9644-0750</orcidid><orcidid>https://orcid.org/0000-0001-8695-2915</orcidid><orcidid>https://orcid.org/0000-0001-5725-0439</orcidid><orcidid>https://orcid.org/0000-0002-1664-1692</orcidid><orcidid>https://orcid.org/0000-0003-0553-4039</orcidid><orcidid>https://orcid.org/0000-0003-0360-6318</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Analgesics - therapeutic use Animals Behavior, Animal - drug effects Female HEK293 Cells Humans Male Nociceptive Pain - drug therapy Nociceptive Pain - metabolism Rats Rats, Sprague-Dawley Receptors, Serotonin - metabolism Secologanin Tryptamine Alkaloids - therapeutic use |
| title | Activity of Mitragyna speciosa (“Kratom”) Alkaloids at Serotonin Receptors |
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