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Moreira, Leandro Andrade - One of the best experts on this subject based on the ideXlab platform.
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Preparação de derivados triptamínicos e dímeros inibidores de acetilcolinesterase a partir da bufotenina isolada de Anadenanthera (Fabaceae: Mimosideae)
2016Co-Authors: Moreira, Leandro AndradeAbstract:O alcaloide indólicobufotenina (5-hidróxi-N,N-dimetiltriptamina) tem sido encontrado em diversas fontes vegetais e animais e, recentemente, vem despertando grande atenção desde a sua detecção em vários fluídos corporais humanos. Esse trabalho descreve um protocolo eficiente para o isolamento da bufotenina de sementes de espécies de Anadenanthera (A. peregrina eA. colubrina), árvores amplamente distribuídas no cerrado brasileiro, e descreve o uso deste alcaloide como matéria-prima apropriada para síntese de vários derivados indólicos com potencial bioativo. A análise química da fração oleaginosa revelou que a composição principal de ácidos graxos insaturados (ácidos oleico e linoleico) sugere elevado valor nutricional das sementes de Anadenanthera. A conversão da bufotenina nos derivados triptamínicosiodeto de 5-hidróxi-N,N,N-trimetiltriptamina (bufotenidina), N,N-dimetiltriptamina (DMT) e 5-metóxi-N,N-dimetiltriptamina (MDMT) foirealizada através deuma rota sintética simplicada e inovadora. Além disso, foi relatado ummétodofácil paraaconversão da bufotenina em um complexo aminoborano inédito. A partir do complexo bufotenina aminoborano foram sintetizados oito dímeros e um derivado oxindólico inéditos. A caracterização estrutural da bufotenina, dos derivados triptamínicos, e oxindólico bem como dos dímeros bis-indólicos foi realizada por CG-MS, FT-IR, RMN 1H e 13C (uni-dimensionais) e HRESI/MS. A bufotenina, bufotenidina e quatros dímeros indólicos foram avaliados como inibidores da acetilcolinesterase (AChE) pelo método da enzima imobilizada em bioreatores capilares acoplados a espectroscopia de massa (AChE-ICERs/LC-MS). Por meio desse estudo, bufotenidina e três dos dímeros testados apresentaram elevada percentagem de inibição da AChE, com destaque para 1,3-bis-((5-metóxi-3-(2-(N,N-dimetil)etilamino)-1H-indol-1-il)propano que exibiu 92,23% de atividade inibitória, maior que a galantamina (90,81 %). ______________________________________________________________________________ ABSTRACTThe indole alkaloid Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been found in several vegetal and animal sources, and recently has been attracted great interest since its detection in humans body fluids. This work describes an effortless and efficient protocol for isolation of Bufotenine from seeds of Anadenanthera species (A. peregrina andA.colubrina), widespread trees in the Brazilian cerrado, and proposes the utilization of this alkaloid as suitable starting material for the synthesis of various potential bioactive indole derivatives. The analyses of the oleaginous fractions revealed that the main fatty acid composition (oleic and linoleic) indicates the nutritional value of the Anadenanthera seeds. The conversion of the Bufotenine tryptamine derivatives into 5-hydroxy-N,N,N-trimethyltryptamine iodide (bufotenidine), N-dimethyltryptamine N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (MDMT) was accomplished through an innovative and short synthetic pathway. Furthermore, it was reported an effortless methodology for conversion of the Bufotenine into the inherit amineborane complex. Starting from Bufotenine-amineborane complex eight new dimers and an oxindole derivative were synthesized. The structural characterization of Bufotenine, tryptamine and oxindole derivatives as well as the bis-indole dimers was accomplished by GC-MS, FT-IR, 1H and 13C NMR (uni and two-dimensional) and HRESI/MS. TheBufotenine, bufotenidine andfour dimerswere evaluatedas inhibitorsof the acetylcholinesterase (AChE)by immobilized capillary enzyme reactor-tandem mass spectroscopy (AChE-ICERs/LC-MS) method. Through this study the tested bufotenidine and three dimers showed great percentage of the AchE inhibition, highlighting for propane-1,3-diylbis(5-methoxy-1H-indole-1,3-diyl))bis(N,N-dimethylethan-1-amine which exhibited 92,23% of inhibitory activity, higher than the galantamine (90,81 %)
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Preparação de derivados triptamínicos e dímeros inibidores de acetilcolinesterase a partir da bufotenina isolada de Anadenanthera (Fabaceae: Mimosideae)
'Biblioteca Central da UNB', 2015Co-Authors: Moreira, Leandro AndradeAbstract:Tese (doutorado)—Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2015.O alcaloide indólicobufotenina (5-hidróxi-N,N-dimetiltriptamina) tem sido encontrado em diversas fontes vegetais e animais e, recentemente, vem despertando grande atenção desde a sua detecção em vários fluídos corporais humanos. Esse trabalho descreve um protocolo eficiente para o isolamento da bufotenina de sementes de espécies de Anadenanthera (A. peregrina eA. colubrina), árvores amplamente distribuídas no cerrado brasileiro, e descreve o uso deste alcaloide como matéria-prima apropriada para síntese de vários derivados indólicos com potencial bioativo. A análise química da fração oleaginosa revelou que a composição principal de ácidos graxos insaturados (ácidos oleico e linoleico) sugere elevado valor nutricional das sementes de Anadenanthera. A conversão da bufotenina nos derivados triptamínicosiodeto de 5-hidróxi-N,N,N-trimetiltriptamina (bufotenidina), N,N-dimetiltriptamina (DMT) e 5-metóxi-N,N-dimetiltriptamina (MDMT) foirealizada através deuma rota sintética simplicada e inovadora. Além disso, foi relatado ummétodofácil paraaconversão da bufotenina em um complexo aminoborano inédito. A partir do complexo bufotenina aminoborano foram sintetizados oito dímeros e um derivado oxindólico inéditos. A caracterização estrutural da bufotenina, dos derivados triptamínicos, e oxindólico bem como dos dímeros bis-indólicos foi realizada por CG-MS, FT-IR, RMN 1H e 13C (uni-dimensionais) e HRESI/MS. A bufotenina, bufotenidina e quatros dímeros indólicos foram avaliados como inibidores da acetilcolinesterase (AChE) pelo método da enzima imobilizada em bioreatores capilares acoplados a espectroscopia de massa (AChE-ICERs/LC-MS). Por meio desse estudo, bufotenidina e três dos dímeros testados apresentaram elevada percentagem de inibição da AChE, com destaque para 1,3-bis-((5-metóxi-3-(2-(N,N-dimetil)etilamino)-1H-indol-1-il)propano que exibiu 92,23% de atividade inibitória, maior que a galantamina (90,81 %).The indole alkaloid Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been found in several vegetal and animal sources, and recently has been attracted great interest since its detection in humans body fluids. This work describes an effortless and efficient protocol for isolation of Bufotenine from seeds of Anadenanthera species (A. peregrina andA.colubrina), widespread trees in the Brazilian cerrado, and proposes the utilization of this alkaloid as suitable starting material for the synthesis of various potential bioactive indole derivatives. The analyses of the oleaginous fractions revealed that the main fatty acid composition (oleic and linoleic) indicates the nutritional value of the Anadenanthera seeds. The conversion of the Bufotenine tryptamine derivatives into 5-hydroxy-N,N,N-trimethyltryptamine iodide (bufotenidine), N-dimethyltryptamine N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (MDMT) was accomplished through an innovative and short synthetic pathway. Furthermore, it was reported an effortless methodology for conversion of the Bufotenine into the inherit amineborane complex. Starting from Bufotenine-amineborane complex eight new dimers and an oxindole derivative were synthesized. The structural characterization of Bufotenine, tryptamine and oxindole derivatives as well as the bis-indole dimers was accomplished by GC-MS, FT-IR, 1H and 13C NMR (uni and two-dimensional) and HRESI/MS. TheBufotenine, bufotenidine andfour dimerswere evaluatedas inhibitorsof the acetylcholinesterase (AChE)by immobilized capillary enzyme reactor-tandem mass spectroscopy (AChE-ICERs/LC-MS) method. Through this study the tested bufotenidine and three dimers showed great percentage of the AchE inhibition, highlighting for propane-1,3-diylbis(5-methoxy-1H-indole-1,3-diyl))bis(N,N-dimethylethan-1-amine which exhibited 92,23% of inhibitory activity, higher than the galantamine (90,81 %)
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Estudos visando a utilização da bufotenina obtida de sementes de Anadenanthera (Fabaceae : Mimosideae) na síntese de derivados triptamínicos
2012Co-Authors: Moreira, Leandro AndradeAbstract:A potencialidade do Cerrado Brasileiro (Savana), como fonte de substâncias interessantes sob o ponto de vista químico e farmacológico, tem estimulado uma série de pesquisas visando à descoberta de novas entidades químicas e o desenvolvimento de fármacos. A quantidade do alcalóide indólico bufotenina em sementes de espécies de Anadenanthera vem despertando especial atenção quanto ao seu potencial como matéria-prima para preparação de derivados triptamínicos capazes de agir sobre sistema nervoso central, de exibir propriedade antimicrobiana, antitumoral ou de atuar como capturadores de radicais livres. Neste trabalho, sementes de duas árvores nativas do gênero, A. peregrina (var. peregrina) e A. peregrina (var. falcata), foram coletadas em dois períodos distintos. O alcalóide bufotenina foi isolado das sementes Anadenanthera com elevado padrão de pureza empregando uma adaptação do método de Stromberg. O alcalóide bufotenina foi isolado das sementes com elevado pureza empregando uma adaptação do método de Stromberg. Transformações químicas realizadas na bufotenina forneceram diversos derivados triptamínicos, os quais foram caracterizados por meio de técnicas de CG-EM, IV, RMN 1H e 13C (uni e bidimensionais). A triagem citotóxica realizada em diferentes linhagens de células tumorais humanas HCT-8 (cólon), SF295 (glioblastoma) e MDA-MB435 (melanoma) por meio do método do MTT mostrou que a bufofetina não é citotóxica enquanto que alguns dos seus derivados exibem potente e seletivo efeito antiproliferativo MDA-MB435, merecendo investigação adicional. Esses dados sugerem que modificações químicas na bufotenina podem fornecer substâncias com atividade antitumoral. A bufotenina juntamente com seus derivados estão sob investigação quanto ao perfil antioxidante. _____________________________________________________________________________ ABSTRACTThe potentiality of the Brazilian Cerrado (Savannah), as source of interesting substances from the point of view chemical and pharmacological, has stimulated a series of researches aiming the discovery of new chemical entities and the development of drugs. The amount of indole alkaloid bufotenin in seeds of Anadenanthera species has attracted special attention regarding its potential as starting material for the preparation of tryptamine derivatives able to act on central nervous system, to exhibit antimicrobial and antitumoral properties or to work like catchers of free radical. In this work, seeds of two native plant of the genus, A. peregrina (var. peregrina) e A. peregrina (var. falcata), were collected in two distinct periods. The alkaloid Bufotenine was isolated from the seeds of Anadenanthera in high purity by using a modification of Stromberg method. Chemical modifications performed on bufotenin furnished several tryptamine derivatives, which were characterizated by GC-EM, FT-IR and RMN 1H and 13C (one and two-dimensional) techniques. The cytotoxicity screening performed in different human cancer cell lines HCT-8 (colon), SF295 (glioblastoma) and MDA-MB435 (melanoma) by the MTT method showed no activity for bufotenin whereas some of its derivatives exhibited potent and selective antiproliferative effect against MDA-MB435, deserving further investigation. These data suggest that chemical modification on bufotenin can provide substances antimural activity. Bufotenin together with its precursors are under investigation concerning the antioxidant profile
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Estudos visando a utilização da bufotenina obtida de sementes de Anadenanthera (Fabaceae : Mimosideae) na síntese de derivados triptamínicos
2011Co-Authors: Moreira, Leandro AndradeAbstract:Dissertação (mestrado)—Universidade de Brasília, Programa de Pós-Graduação em Química, 2011.A potencialidade do Cerrado Brasileiro (Savana), como fonte de substâncias interessantes sob o ponto de vista químico e farmacológico, tem estimulado uma série de pesquisas visando à descoberta de novas entidades químicas e o desenvolvimento de fármacos. A quantidade do alcalóide indólico bufotenina em sementes de espécies de Anadenanthera vem despertando especial atenção quanto ao seu potencial como matéria-prima para preparação de derivados triptamínicos capazes de agir sobre sistema nervoso central, de exibir propriedade antimicrobiana, antitumoral ou de atuar como capturadores de radicais livres. Neste trabalho, sementes de duas árvores nativas do gênero, A. peregrina (var. peregrina) e A. peregrina (var. falcata), foram coletadas em dois períodos distintos. O alcalóide bufotenina foi isolado das sementes Anadenanthera com elevado padrão de pureza empregando uma adaptação do método de Stromberg. O alcalóide bufotenina foi isolado das sementes com elevado pureza empregando uma adaptação do método de Stromberg. Transformações químicas realizadas na bufotenina forneceram diversos derivados triptamínicos, os quais foram caracterizados por meio de técnicas de CG-EM, IV, RMN 1H e 13C (uni e bidimensionais). A triagem citotóxica realizada em diferentes linhagens de células tumorais humanas HCT-8 (cólon), SF295 (glioblastoma) e MDA-MB435 (melanoma) por meio do método do MTT mostrou que a bufofetina não é citotóxica enquanto que alguns dos seus derivados exibem potente e seletivo efeito antiproliferativo MDA-MB435, merecendo investigação adicional. Esses dados sugerem que modificações químicas na bufotenina podem fornecer substâncias com atividade antitumoral. A bufotenina juntamente com seus derivados estão sob investigação quanto ao perfil antioxidante. _____________________________________________________________________________ ABSTRACTThe potentiality of the Brazilian Cerrado (Savannah), as source of interesting substances from the point of view chemical and pharmacological, has stimulated a series of researches aiming the discovery of new chemical entities and the development of drugs. The amount of indole alkaloid bufotenin in seeds of Anadenanthera species has attracted special attention regarding its potential as starting material for the preparation of tryptamine derivatives able to act on central nervous system, to exhibit antimicrobial and antitumoral properties or to work like catchers of free radical. In this work, seeds of two native plant of the genus, A. peregrina (var. peregrina) e A. peregrina (var. falcata), were collected in two distinct periods. The alkaloid Bufotenine was isolated from the seeds of Anadenanthera in high purity by using a modification of Stromberg method. Chemical modifications performed on bufotenin furnished several tryptamine derivatives, which were characterizated by GC-EM, FT-IR and RMN 1H and 13C (one and two-dimensional) techniques. The cytotoxicity screening performed in different human cancer cell lines HCT-8 (colon), SF295 (glioblastoma) and MDA-MB435 (melanoma) by the MTT method showed no activity for bufotenin whereas some of its derivatives exhibited potent and selective antiproliferative effect against MDA-MB435, deserving further investigation. These data suggest that chemical modification on bufotenin can provide substances antimural activity. Bufotenin together with its precursors are under investigation concerning the antioxidant profile
Ramos, Luciana Machado - One of the best experts on this subject based on the ideXlab platform.
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Obtenção do alcalóide indólico bufotenina de sementes de Anadenanthera sp (Fabaceae: Mimosideae) do bioma Cerrado e sua utilização para síntese de substâncias bioativas
2010Co-Authors: Ramos, Luciana MachadoAbstract:O bioma Cerrado Brasileiro tem uma grande variedade de espécies vegetais ricas em substâncias químicas orgânicas de interesse, especialmente alcalóides, encontradas em diferentes teores nas folhas, frutos, caules, raízes e sementes. O presente estudo incidiu sobre a fitoquímica da Anadenanthera (Fabaceae: Mimosoideae), uma árvore perene generalizada no Cerrado Brasileiro, conhecida popularmente como angico-do-cerrado, angico-cascudo, angico-do-campo e arapiraca. Uma atenção especial foi destinada ao estudo comparativo do alcalóide indólico bufotenina em sementes de diferentes espécies de Anadenanthera e investigação de seu potencial como matéria-prima para preparação de análogos da serotonina que exibem atividade antimicrobiana, antitumoral e capturadores de radicais livres, assim como derivados tetrahidro-β-carbolina capazes de atuar no sistema nervoso central. Partes das plantas (folhas, flores, caule e sementes) de espécies do gênero Anadenanthera foram coletadas de agosto a setembro de 2006, nos arredores de Brasília. Exsicatas foram preparadas e depositadas no Herbário da Universidade de Brasília. As espécies coletadas foram identificadas como sendo Anadenanthera peregrina (vars. peregrina e falcata) e Anadenanthera colubrina (var. cebil). As sementes foram submetidas a diversos métodos extrativos. O extrato etanólico (Soxhlet) das sementes apresentou uma fração menos polar e abundante composta basicamente por triglicerídeos de ácidos graxos e uma fração mais polar constituída apenas pelo alcalóide indólico bufotenina. O método de Stromberg demonstrou ser um método mais eficiente para a extração, purificação e quantificação da bufotenina. A presença de bufotenina em extratos das variedades foi confirmada por FT-IR, RMN H1, RMN C13 e CG-EM. O estudo fitoquímico confirmou que estas espécies são fontes promissoras da bufotenina (cerca de 2,9%) e a literatura sugere que modificações estruturais adequadas na bufotenina podem fornecer compostos com elevado potencial bioativo. __________________________________________________________________________________________ ABSTRACTThe biome Brazilian Cerrado (Savannah) has a variety of plant species rich in organic chemicals of interest, especially alkaloids, found at different levels in the leaves, fruits, stems, roots and seeds. The current study focused on the phytochemistry of the Anadenanthera (Leguminosae: Mimosoideae), a perennial tree widespread in the Brazilian Cerrado, popularly known as angico-do-cerrado, angico-cascudo, angico-do-campo and arapiraca. Special emphasis was intended for comparative investigation of the indole alkaloid Bufotenine in seeds of different species of Anadenanthera and its potential utilization as raw-material for the preparation of serotonin analogous, which have shown to exhibit antimicrobiana, antitumoral and free radical scavenging activities as well as tetrahydro-β-carboline derivatives which can be active in the central nervous system. Parts of the plants (leaves, stems, flowers, and seeds) of the genus Anadenanthera were collected around Brasilia from august to setember, 2006, vouchers were prepared and deposited in the University of Brasilia Herbarium. The species were identified as Anadenanthera peregrina (vars. peregrina and falcata) and Anadenanthera columbrina (var. cebil). Seeds were submited to different extraction metodologies. The seed ethanolic extract (Soxhlet) shown a less polar and abundant fraction that the main chemical components are triglycerides of fatty acids and a more polar fraction constituted only by the indole alkaloid bufotenin. The Stromberg method’s shown to be a more efficient methodology for extraction, purification and quantification of the Bufotenine. The presence of Bufotenine in extracts of these varieties was confirmed for FT-IR, 1H NMR, 13C NMR, and GC-MS. The phytochemical study confirmed that these species are promising source of the Bufotenine (about 2,9%) and the literature suggests that appropriate structural modifications on Bufotenine may afford potential bioactive compounds
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Obtenção do alcalóide indólico bufotenina de sementes de Anadenanthera sp (Fabaceae: Mimosideae) do bioma Cerrado e sua utilização para síntese de substâncias bioativas
2008Co-Authors: Ramos, Luciana MachadoAbstract:Dissertação (mestrado)—Universidade de Brasília, Instituto de Química, 2008.O bioma Cerrado Brasileiro tem uma grande variedade de espécies vegetais ricas em substâncias químicas orgânicas de interesse, especialmente alcalóides, encontradas em diferentes teores nas folhas, frutos, caules, raízes e sementes. O presente estudo incidiu sobre a fitoquímica da Anadenanthera (Fabaceae: Mimosoideae), uma árvore perene generalizada no Cerrado Brasileiro, conhecida popularmente como angico-do-cerrado, angico-cascudo, angico-do-campo e arapiraca. Uma atenção especial foi destinada ao estudo comparativo do alcalóide indólico bufotenina em sementes de diferentes espécies de Anadenanthera e investigação de seu potencial como matéria-prima para preparação de análogos da serotonina que exibem atividade antimicrobiana, antitumoral e capturadores de radicais livres, assim como derivados tetrahidro-β-carbolina capazes de atuar no sistema nervoso central. Partes das plantas (folhas, flores, caule e sementes) de espécies do gênero Anadenanthera foram coletadas de agosto a setembro de 2006, nos arredores de Brasília. Exsicatas foram preparadas e depositadas no Herbário da Universidade de Brasília. As espécies coletadas foram identificadas como sendo Anadenanthera peregrina (vars. peregrina e falcata) e Anadenanthera colubrina (var. cebil). As sementes foram submetidas a diversos métodos extrativos. O extrato etanólico (Soxhlet) das sementes apresentou uma fração menos polar e abundante composta basicamente por triglicerídeos de ácidos graxos e uma fração mais polar constituída apenas pelo alcalóide indólico bufotenina. O método de Stromberg demonstrou ser um método mais eficiente para a extração, purificação e quantificação da bufotenina. A presença de bufotenina em extratos das variedades foi confirmada por FT-IR, RMN H1, RMN C13 e CG-EM. O estudo fitoquímico confirmou que estas espécies são fontes promissoras da bufotenina (cerca de 2,9%) e a literatura sugere que modificações estruturais adequadas na bufotenina podem fornecer compostos com elevado potencial bioativo. __________________________________________________________________________________________ ABSTRACTThe biome Brazilian Cerrado (Savannah) has a variety of plant species rich in organic chemicals of interest, especially alkaloids, found at different levels in the leaves, fruits, stems, roots and seeds. The current study focused on the phytochemistry of the Anadenanthera (Leguminosae: Mimosoideae), a perennial tree widespread in the Brazilian Cerrado, popularly known as angico-do-cerrado, angico-cascudo, angico-do-campo and arapiraca. Special emphasis was intended for comparative investigation of the indole alkaloid Bufotenine in seeds of different species of Anadenanthera and its potential utilization as raw-material for the preparation of serotonin analogous, which have shown to exhibit antimicrobiana, antitumoral and free radical scavenging activities as well as tetrahydro-β-carboline derivatives which can be active in the central nervous system. Parts of the plants (leaves, stems, flowers, and seeds) of the genus Anadenanthera were collected around Brasilia from august to setember, 2006, vouchers were prepared and deposited in the University of Brasilia Herbarium. The species were identified as Anadenanthera peregrina (vars. peregrina and falcata) and Anadenanthera columbrina (var. cebil). Seeds were submited to different extraction metodologies. The seed ethanolic extract (Soxhlet) shown a less polar and abundant fraction that the main chemical components are triglycerides of fatty acids and a more polar fraction constituted only by the indole alkaloid bufotenin. The Stromberg method’s shown to be a more efficient methodology for extraction, purification and quantification of the Bufotenine. The presence of Bufotenine in extracts of these varieties was confirmed for FT-IR, 1H NMR, 13C NMR, and GC-MS. The phytochemical study confirmed that these species are promising source of the Bufotenine (about 2,9%) and the literature suggests that appropriate structural modifications on Bufotenine may afford potential bioactive compounds
Xi Ling Jiang - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status
Drug metabolism and disposition: the biological fate of chemicals, 2013Co-Authors: Xi Ling Jiang, Hong Wu Shen, Donald E. MagerAbstract:5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name “5-MEO”) is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite Bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce Bufotenine. Our data revealed that inhibition of MAO-A–mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain Bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced Bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed Bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and Bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline–5-MeO-DMT pharmacodynamics.
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Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions.
Current drug metabolism, 2010Co-Authors: Hong Wu Shen, Xi Ling Jiang, Jerrold C. WinterAbstract:5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, Bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite Bufotenine. Harmaline, 5-MeO-DMT and Bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.
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effects of monoamine oxidase inhibitor and cytochrome p450 2d6 status on 5 methoxy n n dimethyltryptamine metabolism and pharmacokinetics
Biochemical Pharmacology, 2010Co-Authors: Hong Wu Shen, Xi Ling JiangAbstract:5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite Bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibitor (MAOI) on 5-MeO-DMT metabolism and pharmacokinetics. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes showed that CYP2D6.2 and CYP2D6.10 exhibited 2.6- and 40-fold lower catalytic efficiency (V(max)/K(m)), respectively, in producing Bufotenine from 5-MeO-DMT, compared with wild-type CYP2D6.1. When co-incubated with MAOI pargyline, 5-MeO-DMT O-demethylation in 10 human liver microsomes showed significantly strong correlation with bufuralol 1'-hydroxylase activities (R(2)=0.98; P<0.0001) and CYP2D6 contents (R(2)=0.77; P=0.0007), whereas no appreciable correlations with enzymatic activities of other P450 enzymes. Furthermore, concurrent MAOI harmaline sharply reduced 5-MeO-DMT depletion and increased Bufotenine formation in human CYP2D6 extensive metabolizer hepatocytes. In vivo studies in wild-type and CYP2D6-humanized (Tg-CYP2D6) mouse models showed that Tg-CYP2D6 mice receiving the same dose of 5-MeO-DMT (20mg/kg, i.p.) had 60% higher systemic exposure to metabolite Bufotenine. In addition, pretreatment of harmaline (5mg/kg, i.p.) led to 3.6- and 4.4-fold higher systemic exposure to 5-MeO-DMT (2mg/kg, i.p.), and 9.9- and 6.1-fold higher systemic exposure to Bufotenine in Tg-CYP2D6 and wild-type mice, respectively. These findings indicate that MAOI largely affects 5-MeO-DMT metabolism and pharmacokinetics, as well as Bufotenine formation that is mediated by CYP2D6.
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Development of a LC-MS/MS method to analyze 5-methoxy-N,N-dimethyltryptamine and Bufotenine, and application to pharmacokinetic study.
Bioanalysis, 2009Co-Authors: Hong Wu Shen, Xi Ling JiangAbstract:INTRODUCTION: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive indolealkylamine substance that has been used for recreational purpose and may lead to fatal toxicity. While 5-MeO-DMT is mainly inactivated via deamination, it is O-demethylated to an active metabolite, Bufotenine. Quantitation of 5-MeO-DMT and Bufotenine is essential to understand the exposure to and the effects of drug and metabolite. This study, therefore, aimed to develop and validate a LC-MS/MS method for simultaneous analysis of 5-MeO-DMT and Bufotenine in mouse serum. METHODS: A simple protein precipitation method coupled with an optimal gradient elution was used for sample preparation and separation. Detection of 5-MeO-DMT and Bufotenine was accomplished using multiple reaction monitoring of m/z 219.2→174.2 and 205.2→160.2, respectively, in the positive ion mode. 5-Methyl-N,N-dimethyltrypamine (m/z 203.2→158.3) was used as internal standard for quantification. Accuracy and precision were determined after the analyses of quality control samples. Validated assay was then employed to determine drug and metabolite concentrations in serum samples collected from mice at different time points after intraperitoneal administration of 5-MeO-DMT (2 mg/kg). RESULTS: With a total run time of 9 min, 5-MeO-DMT and Bufotenine were eluted at 2.8 and 5.6 min, respectively. The assay was linear over the range 0.90-5,890 ng/mL (1.12-7,360 pg on-column) for 5-MeO-DMT and 2.52-5,510 ng/mL (3.14-6,890 pg) for Bufotenine. Intra- and inter-day precision and accuracy were within 15% for both analytes. The recovery of each analyte from 20 µL of serum containing 8.08, 72.7 and 655 ng/mL of 5-MeO-DMT and 7.56, 68.1 and 613 ng/mL of Bufotenine was more than 75%. Pharmacokinetic analysis revealed that the systemic exposure (area under the curve) to metabolite Bufotenine was about 1/14 of that to 5-MeO-DMT. CONCLUSION: This LC-MS/MS method is a sensitive and reliable assay for quantitation of blood 5-MeO-DMT and Bufotenine. Given the fact that Bufotenine acts on 5-HT(2A) receptor with an affinity about 10-fold higher than 5-MeO-DMT, the active metabolite Bufotenine may significantly contribute to the apparent pharmacological and toxicological effects of 5-MeO-DMT.
Michel Pfau - One of the best experts on this subject based on the ideXlab platform.
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Aromatization of 1,6,7,7a-tetrahydro-2H-indol-2-ones by a novel process. Preparation of key-intermediate methyl 1-benzyl-5-methoxy-1H-indole-3-acetate and the syntheses of serotonin, melatonin, and bufotenin.
The Journal of Organic Chemistry, 2002Co-Authors: Gilbert Revial, Ivan Jabin, Sethy Lim, Michel PfauAbstract:Imine 7 of 1,4-cyclohexanedione mono-ethylene ketal 6 was reacted with maleic anhydride, affording the cyclized adduct 8. Methyl esterification of 8, accompanied by transacetalization, led to the dihydrooxindole derivative 10. Aromatization of 10 was then accomplished with POCl(3), leading directly to the key-intermediate title compound 11 in 74% yield from ketone 6. Serotonin, melatonin, and bufotenin were then obtained by standard reactions.
Minggang Wang - One of the best experts on this subject based on the ideXlab platform.
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desmodeleganine a new alkaloid from the leaves of desmodium elegans as a potential monoamine oxidase inhibitor
Fitoterapia, 2014Co-Authors: Kangkang Zhi, Zhongduo Yang, Danfeng Shi, Xiaojun Yao, Minggang WangAbstract:Abstract Desmodeleganine (1), a new potential monoamine oxidase inhibitor, along with three known alkaloids, bufotenin (2), hydroxy-N, N-dimethyltryptamine N12-oxide (3), 2-(5-methoxy-1H-indol-3-yl)-N, and N-dimethylethylamine (4) were isolated from the leaves of Desmodium elegans. Their structures were elucidated by IR, MS, 1D and 2D NMR spectra. 1 showed strong monoamine oxidase inhibitory activity with IC50 value of 13.92 ± 1.5 μM, when the IC50 value of iproniazid as a standard was 6.5 ± 0.5 μM. The molecular modeling was also performed to explore the binding mode of compounds 1, 2 at the active site of MAO-A and MAO-B.
