Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation
The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investiga...
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| creator | Antonio, Tamara Childers, Steven R Rothman, Richard B Dersch, Christina M King, Christine Kuehne, Martin Bornmann, William G Eshleman, Amy J Janowsky, Aaron Simon, Eric R Reith, Maarten E A Alper, Kenneth |
| description | The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.
Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.
In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids. |
| doi_str_mv | 10.1371/journal.pone.0077262 |
| format | Article |
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Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.
In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0077262</identifier><identifier>PMID: 24204784</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Addictions ; Alkaloids ; Animal models ; Animals ; Antagonists ; Autoradiography ; Binding ; Biochemistry ; Brain ; Brain research ; Brain slice preparation ; Bridged-Ring Compounds - pharmacology ; CHO Cells ; Cricetulus ; Detoxification ; Dopamine ; Dose-Response Relationship, Drug ; Drug abuse ; Drug dosages ; Drug self-administration ; Drug therapy ; Drug tolerance ; Female ; Gene Expression ; Guanosine ; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology ; HEK293 Cells ; Humans ; Ibogaine ; Ibogaine - analogs & derivatives ; Ibogaine - pharmacology ; Medicine ; Membranes ; Narcotics ; Neurosciences ; Opioid receptors ; Organ Specificity ; Pharmacology ; Proteins ; Psychiatry ; Psychopharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu - agonists ; Receptors, Opioid, mu - antagonists & inhibitors ; Receptors, Opioid, mu - genetics ; Receptors, Opioid, mu - metabolism ; Substance abuse treatment ; Substance Withdrawal Syndrome - prevention & control ; Thalamus ; Thalamus - drug effects ; Thalamus - metabolism ; Withdrawal</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e77262</ispartof><rights>2013 Antonio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Antonio et al 2013 Antonio et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-911674e81346f235e069ede4a1ddea029cd19090fa9471ce7e645f00532901893</citedby><cites>FETCH-LOGICAL-c526t-911674e81346f235e069ede4a1ddea029cd19090fa9471ce7e645f00532901893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818563/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818563/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24204784$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Antonio, Tamara</creatorcontrib><creatorcontrib>Childers, Steven R</creatorcontrib><creatorcontrib>Rothman, Richard B</creatorcontrib><creatorcontrib>Dersch, Christina M</creatorcontrib><creatorcontrib>King, Christine</creatorcontrib><creatorcontrib>Kuehne, Martin</creatorcontrib><creatorcontrib>Bornmann, William G</creatorcontrib><creatorcontrib>Eshleman, Amy J</creatorcontrib><creatorcontrib>Janowsky, Aaron</creatorcontrib><creatorcontrib>Simon, Eric R</creatorcontrib><creatorcontrib>Reith, Maarten E A</creatorcontrib><creatorcontrib>Alper, Kenneth</creatorcontrib><title>Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.
Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.
In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.</description><subject>Activation</subject><subject>Addictions</subject><subject>Alkaloids</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Autoradiography</subject><subject>Binding</subject><subject>Biochemistry</subject><subject>Brain</subject><subject>Brain research</subject><subject>Brain slice preparation</subject><subject>Bridged-Ring Compounds - pharmacology</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Detoxification</subject><subject>Dopamine</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug abuse</subject><subject>Drug dosages</subject><subject>Drug self-administration</subject><subject>Drug therapy</subject><subject>Drug tolerance</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Guanosine</subject><subject>Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Ibogaine</subject><subject>Ibogaine - analogs & derivatives</subject><subject>Ibogaine - pharmacology</subject><subject>Medicine</subject><subject>Membranes</subject><subject>Narcotics</subject><subject>Neurosciences</subject><subject>Opioid receptors</subject><subject>Organ Specificity</subject><subject>Pharmacology</subject><subject>Proteins</subject><subject>Psychiatry</subject><subject>Psychopharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Opioid, mu - agonists</subject><subject>Receptors, Opioid, mu - antagonists & inhibitors</subject><subject>Receptors, Opioid, mu - genetics</subject><subject>Receptors, Opioid, mu - metabolism</subject><subject>Substance abuse treatment</subject><subject>Substance Withdrawal Syndrome - prevention & control</subject><subject>Thalamus</subject><subject>Thalamus - drug effects</subject><subject>Thalamus - metabolism</subject><subject>Withdrawal</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUstu1DAUjRCoL_oHCCKx6SaDX7HjDVJVtWWkkdjA2rpj3wwePHGwk0p8GD_AlzXTSasWsfK1fc65516donhHyYJyRT9t45g6CIs-drggRCkm2avihGrOKskIf_2sPi5Oc94SUvNGyqPimAlGhGrESbG6blu0QxnbcrmOGygh_IQQvctl7Mq_f6rY--lWJrTYDzFVNo59QFfeln2KA_quBDv4Oxh87N4Wb1oIGc_n86z4fnP97epLtfp6u7y6XFW2ZnKoNKVSCWwoF7JlvEYiNToUQJ1DIExbRzXRpAUtFLWoUIq63btnmtBG87Piw0G3DzGbeRHZUCGYkLKWfEIsDwgXYWv65HeQfpsI3jw8xLQxkAZvAxpaO0drJYFLEBYBGNfQOIJSEiXWYtL6PHcb1zt0FrshQXgh-vKn8z_MJt4Z3tDmYOZiFkjx14h5MDufLYYAHcbxwbdWsqlFPUE__gP9_3TigLIp5pywfTJDidmH45Fl9uEwczgm2vvngzyRHtPA7wFU0LdR</recordid><startdate>20131016</startdate><enddate>20131016</enddate><creator>Antonio, Tamara</creator><creator>Childers, Steven R</creator><creator>Rothman, Richard B</creator><creator>Dersch, Christina M</creator><creator>King, Christine</creator><creator>Kuehne, Martin</creator><creator>Bornmann, William G</creator><creator>Eshleman, Amy J</creator><creator>Janowsky, Aaron</creator><creator>Simon, Eric R</creator><creator>Reith, Maarten E A</creator><creator>Alper, Kenneth</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131016</creationdate><title>Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation</title><author>Antonio, Tamara ; Childers, Steven R ; Rothman, Richard B ; Dersch, Christina M ; King, Christine ; Kuehne, Martin ; Bornmann, William G ; Eshleman, Amy J ; Janowsky, Aaron ; Simon, Eric R ; Reith, Maarten E A ; Alper, Kenneth</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-911674e81346f235e069ede4a1ddea029cd19090fa9471ce7e645f00532901893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Activation</topic><topic>Addictions</topic><topic>Alkaloids</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antagonists</topic><topic>Autoradiography</topic><topic>Binding</topic><topic>Biochemistry</topic><topic>Brain</topic><topic>Brain research</topic><topic>Brain slice preparation</topic><topic>Bridged-Ring Compounds - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Antonio, Tamara</au><au>Childers, Steven R</au><au>Rothman, Richard B</au><au>Dersch, Christina M</au><au>King, Christine</au><au>Kuehne, Martin</au><au>Bornmann, William G</au><au>Eshleman, Amy J</au><au>Janowsky, Aaron</au><au>Simon, Eric R</au><au>Reith, Maarten E A</au><au>Alper, Kenneth</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-10-16</date><risdate>2013</risdate><volume>8</volume><issue>10</issue><spage>e77262</spage><pages>e77262-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.
Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.
In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24204784</pmid><doi>10.1371/journal.pone.0077262</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-10, Vol.8 (10), p.e77262 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1442466563 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Activation Addictions Alkaloids Animal models Animals Antagonists Autoradiography Binding Biochemistry Brain Brain research Brain slice preparation Bridged-Ring Compounds - pharmacology CHO Cells Cricetulus Detoxification Dopamine Dose-Response Relationship, Drug Drug abuse Drug dosages Drug self-administration Drug therapy Drug tolerance Female Gene Expression Guanosine Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology HEK293 Cells Humans Ibogaine Ibogaine - analogs & derivatives Ibogaine - pharmacology Medicine Membranes Narcotics Neurosciences Opioid receptors Organ Specificity Pharmacology Proteins Psychiatry Psychopharmacology Rats Rats, Sprague-Dawley Receptors, Opioid, mu - agonists Receptors, Opioid, mu - antagonists & inhibitors Receptors, Opioid, mu - genetics Receptors, Opioid, mu - metabolism Substance abuse treatment Substance Withdrawal Syndrome - prevention & control Thalamus Thalamus - drug effects Thalamus - metabolism Withdrawal |
| title | Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T21%3A14%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Effect%20of%20Iboga%20alkaloids%20on%20%C2%B5-opioid%20receptor-coupled%20G%20protein%20activation&rft.jtitle=PloS%20one&rft.au=Antonio,%20Tamara&rft.date=2013-10-16&rft.volume=8&rft.issue=10&rft.spage=e77262&rft.pages=e77262-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0077262&rft_dat=%3Cproquest_plos_%3E1449768545%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1442466563&rft_id=info:pmid/24204784&rft_doaj_id=oai_doaj_org_article_15dd1576a36a4ceaa239a8d0e66074b4&rfr_iscdi=true |