O triptofano (Trp) é essencial para muitos processos fisiológicos e seu metabolismo apresenta-se alterado em doenças como no câncer. O Trp é degradado por três vias: via das quinureninas; via serotonérgica e via das triptaminas. A primeira está envolvida com a tolerância e o imune escape de células tumorais, já a segunda leva a produção de serotonina e melatonina, com uma diversidade de funções biológicas e que possuem atividades antitumorais reconhecidas. A terceira rota é a menos estudada e a função dos compostos sintetizados ainda é desconhecida. Trabalhos do grupo mostram que a via das triptaminas é ativa em melanomas e que triptamina (TRY) e dimetiltriptamina (DMT), metabólitos produzidos por esta via, também possuem atividade antitumoral. Nosso objetivo é avançar sobre a compreensão de como esta via afeta o metabolismo e crescimento tumoral. Para tanto, estudamos mais detalhadamente a via em linhagens de melanoma. A adição de TRY e DMT nas culturas modificou a produção de compostos das outras rotas de metabolização do Trp. Além disso, TRY e DMT afetaram a invasividade das células tumorais e TRY aumentou a atividade citotóxica de células mononucleares frente a melanomas. Observamos que apesar dos efeitos biológicos da via das quinureninas estar amplamente relacionado a ligação dos metabólitos no receptor de aril hidrocarbonetos, para a via das triptaminas o receptor parece não estar associado com a atividade antitumoral descrita. Nossos resultados apontam para a importância da via das triptaminas na dinâmica tumoral e a necessidade de estudos mais amplos relacionados ao metabolismo do Trp. / Tryptophan (Trp) is essential for many physiological processes and its metabolism is modified in several diseases such as in cancer. TRP is broken down into three pathways: kynurenine path, serotonergic path and tryptamine path. The first is involved in tolerance and immune escape of cancer cells, while the second leads to the production of serotonin and melatonin, which have a variety of biological functions and recognized antitumor activity. The third route is the least studied and the biological function of the synthesized compounds is still unknown. Our group shows that tryptamine path is active in melanomas and tryptamine (TRY) and dimethyltryptamine (DMT), metabolites produced by this route, also have antitumor activity. Our goal is make progress on understanding how tryptamine route affects metabolism and tumor growth. Therefore, we studied in detail this pathway in melanoma cell lines. The addition of TRY and DMT into the cultures leds the production of metabolites of other Trp routes. Moreover, TRY and DMT affect the invasiveness of tumor cells and TRY increased antitumor activity of the immune system against melanomas. We observed that despite biological effects of kynurenine path be largely related to metabolites binding aryl hydrocarbon receptor, for tryptamine pathway the receptor seems not to be associated with the described antitumor activity. Our results point the importance of tryptamine pathway in tumor dynamics and the need for broader studies related to Trp metabolism.

O triptofano (Trp) é essencial para muitos processos fisiológicos e seu metabolismo apresenta-se alterado em doenças como no câncer. O Trp é degradado por três vias: via das quinureninas; via serotonérgica e via das triptaminas. A primeira está envolvida com a tolerância e o imune escape de células tumorais, já a segunda leva a produção de serotonina e melatonina, com uma diversidade de funções biológicas e que possuem atividades antitumorais reconhecidas. A terceira rota é a menos estudada e a função dos compostos sintetizados ainda é desconhecida. Trabalhos do grupo mostram que a via das triptaminas é ativa em melanomas e que triptamina (TRY) e dimetiltriptamina (DMT), metabólitos produzidos por esta via, também possuem atividade antitumoral. Nosso objetivo é avançar sobre a compreensão de como esta via afeta o metabolismo e crescimento tumoral. Para tanto, estudamos mais detalhadamente a via em linhagens de melanoma. A adição de TRY e DMT nas culturas modificou a produção de compostos das outras rotas de metabolização do Trp. Além disso, TRY e DMT afetaram a invasividade das células tumorais e TRY aumentou a atividade citotóxica de células mononucleares frente a melanomas. Observamos que apesar dos efeitos biológicos da via das quinureninas estar amplamente relacionado a ligação dos metabólitos no receptor de aril hidrocarbonetos, para a via das triptaminas o receptor parece não estar associado com a atividade antitumoral descrita. Nossos resultados apontam para a importância da via das triptaminas na dinâmica tumoral e a necessidade de estudos mais amplos relacionados ao metabolismo do Trp. / Tryptophan (Trp) is essential for many physiological processes and its metabolism is modified in several diseases such as in cancer. TRP is broken down into three pathways: kynurenine path, serotonergic path and tryptamine path. The first is involved in tolerance and immune escape of cancer cells, while the second leads to the production of serotonin and melatonin, which have a variety of biological functions and recognized antitumor activity. The third route is the least studied and the biological function of the synthesized compounds is still unknown. Our group shows that tryptamine path is active in melanomas and tryptamine (TRY) and dimethyltryptamine (DMT), metabolites produced by this route, also have antitumor activity. Our goal is make progress on understanding how tryptamine route affects metabolism and tumor growth. Therefore, we studied in detail this pathway in melanoma cell lines. The addition of TRY and DMT into the cultures leds the production of metabolites of other Trp routes. Moreover, TRY and DMT affect the invasiveness of tumor cells and TRY increased antitumor activity of the immune system against melanomas. We observed that despite biological effects of kynurenine path be largely related to metabolites binding aryl hydrocarbon receptor, for tryptamine pathway the receptor seems not to be associated with the described antitumor activity. Our results point the importance of tryptamine pathway in tumor dynamics and the need for broader studies related to Trp metabolism.

Serotonin was first discovered in the late 1940s as a vasotonic factor and is now considered a principal neurotransmitter in the nervous system. 5-HT6 receptors are one of the most recently identified members of the serotonin receptor family which consists of seven classes (5-HT1-5-HT7). 5-HT6 receptors are G-protein coupled, positively coupled to an adenylate cyclase second messenger system and are primarily found in the central nervous system (CNS). The exact functional role of 5-HT6 receptors has not been determined, but is implicated to have possible involvement in certain neuropsychiatric disorders and cognition. To investigate the functional role of these receptors, it is useful to identify 5-HT6 selective ligands as pharmacological tools. Our laboratory identified one of the first 5-HT6 receptor antagonists: the arylsulfonamide MS-245 (14a). It has been assumed that a sulfonyl (i.e., SO2) moiety is important for the binding of arylsulfonamides at 5-HT6 receptors. We now have identified benzyl analog 33 (R=H) as a single example of a non-sulfonyl analog that retains affinity. This questions the importance of the SO2 group and whether an aryl moiety or other hydrophobic groups (of equal or greater hydrophibicity) is required for binding. The purpose of the present investigation was to determine if the SO2, and the aryl moieties are required for high affinity binding. N1-Alkylsulfonyl- 78, and N1-benzyl-substituted tryptamines 33 were synthesized and affinities compared with their corresponding N1-benzenesulfonyl-substituted counterparts 31 at h5-HT6 receptors. None of the alkylsulfonyl or benzyl analogs displayed and/or retained the affinity of the simple benzenesulfonyl tryptamine analog (31a) (Ki = 4.1 nM). The results show that an arylsulfonyl group at the tryptamine N1 position is optimal, relative to an alkylsulfonyl group, for 5-HT6 receptor affinity. In a comparative analysis utilizing six pairs of tryptamines, it was found that there was little correspondence (r2 = 0.048) between the 5-HT6 receptor affinities of the examined benzyl and benzenesulfonyl pairs. Current findings indicate that an aryl (or substituted aryl)sulfonyl (rather than benzyl) moiety is optimal for high affinity binding, and further suggest that N1-benzenesulfonyl- and their corresponding N1-benzyltryptamine counterparts bind in a different fashion.

A enzima indolamina 2,3-dioxigenase (IDO) é responsável pela degradação de triptofano (TRP) pela via das quinureninas. O aumento da expressão de IDO é a grande responsável pela resposta de tolerância imunológica e pode ser induzida por IFN-γ e lipopolissacarídeos (LPS). É conhecido que a IDO participa do mecanismo de imuno escape de células tumorais, sendo relatada como marcadora de progressão tumoral. Desta forma, a inibição da atividade da IDO para a restauração da imunidade anti-tumoral do hospedeiro tem sido considerada uma estratégia para a terapêutica antineoplásica. N,N-dimetiltriptamina (DMT) e triptamina (TRY) são compostos indólicos de origem endógena, provenientes de uma rota paralela de metabolismo do triptofano - a rota das triptaminas, que ocorre principalmente no sistema nervoso central. O presente estudo teve como objetivo avaliar se DMT e TRY modulariam a atividade de IDO. Os resultados obtidos demonstraram ações inibitórias para ambos os compostos e as cinéticas enzimáticas revelaram Ki de 506µM para o DMT e de 156µM para a TRY, com perfis inibitórios característicos de inibidores não-competitivos clássicos. A atividade inibitória foi também observada sobre a enzima IDO expressa constitutivamente, ou induzida por IFN-γ, em células da linhagem de glioblastoma humano A172. Nesta mesma linhagem, em estudo paralelo do grupo, foi avaliada a influência de DMT e TRY sobre a expressão gênica da enzima IDO. Concluímos que nas células a ação inibitória dos compostos avaliados é exercida diretamente sobre sua atividade enzimática, sem redução de sua transcrição. Os resultados deste estudo também serviram como base para estudos da atividade inibitória da DMT e TRY em sistema de co-cultura das células A172 com células mononucleares humanas, onde foi observada redução significativa da atividade enzimática e da proliferação das células tumorais. Em conclusão mostramos a possibilidade de que a via das triptaminas, através de seus metabólitos, possa contribuir com a regulação endógena da via das quinureninas e que o DMT e a TRY deveriam ser avaliados como candidatos a inibidores farmacológicos da enzima IDO e/ou como protótipos para a síntese de novos inibidores. / Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme via the kynurenine pathway. Increased IDO expression is largely responsible for the immune tolerance response and can be induced by IFN-γ and lipopolysaccharide (LPS). It is known that IDO participates in the mechanism of tumor immune tolerance and have been reported as a tumor progression marker. Thus, to restore the anti-tumor immunity of the host, IDO inhibition has been considered as a strategy for anticancer therapy. N, N-dimethyltryptamine (DMT) and tryptamine (TRY) are endogenous indolic compounds originated from a parallel route of tryptophan metabolism - the tryptamines route, which occurs mainly in the central nervous system. This study aimed to assess whether DMT and TRY modulate the IDO activity. The results showed inhibitory actions for both compounds and enzyme kinetics revealed Ki = 506µM to DMT and Ki = 156µM to TRY, with inhibitory profiles characteristic of classical non-competitive inhibitors. The inhibitory activity was also observed on the IDO constitutively expressed or induced by IFN-γ in A172 human glioblastom cell line. Using the same line, in parallel group study, we evaluated the influence of DMT and TRY on the IDO gene expression. We conclude that in cells the evaluated compounds inhibitory action is exerted directly on its enzymatic activity without reduction of its transcription. The results of this study also served as the basis for studies of DMT and TRY inhibitory activity in A172 cells with human mononuclear cells co-culture system, in which was observed significant reduction in enzyme activity and tumor cells proliferation. In conclusion we show the possibility that the tryptamines route, through its metabolites, may contribute to quinurenines pathway endogenous regulation and that DMT and TRY should be evaluated as IDO pharmacological inhibitors candidates and / or as prototypes to new inhibitors synthesis.

A enzima indolamina 2,3-dioxigenase (IDO) é responsável pela degradação de triptofano (TRP) pela via das quinureninas. O aumento da expressão de IDO é a grande responsável pela resposta de tolerância imunológica e pode ser induzida por IFN-γ e lipopolissacarídeos (LPS). É conhecido que a IDO participa do mecanismo de imuno escape de células tumorais, sendo relatada como marcadora de progressão tumoral. Desta forma, a inibição da atividade da IDO para a restauração da imunidade anti-tumoral do hospedeiro tem sido considerada uma estratégia para a terapêutica antineoplásica. N,N-dimetiltriptamina (DMT) e triptamina (TRY) são compostos indólicos de origem endógena, provenientes de uma rota paralela de metabolismo do triptofano - a rota das triptaminas, que ocorre principalmente no sistema nervoso central. O presente estudo teve como objetivo avaliar se DMT e TRY modulariam a atividade de IDO. Os resultados obtidos demonstraram ações inibitórias para ambos os compostos e as cinéticas enzimáticas revelaram Ki de 506µM para o DMT e de 156µM para a TRY, com perfis inibitórios característicos de inibidores não-competitivos clássicos. A atividade inibitória foi também observada sobre a enzima IDO expressa constitutivamente, ou induzida por IFN-γ, em células da linhagem de glioblastoma humano A172. Nesta mesma linhagem, em estudo paralelo do grupo, foi avaliada a influência de DMT e TRY sobre a expressão gênica da enzima IDO. Concluímos que nas células a ação inibitória dos compostos avaliados é exercida diretamente sobre sua atividade enzimática, sem redução de sua transcrição. Os resultados deste estudo também serviram como base para estudos da atividade inibitória da DMT e TRY em sistema de co-cultura das células A172 com células mononucleares humanas, onde foi observada redução significativa da atividade enzimática e da proliferação das células tumorais. Em conclusão mostramos a possibilidade de que a via das triptaminas, através de seus metabólitos, possa contribuir com a regulação endógena da via das quinureninas e que o DMT e a TRY deveriam ser avaliados como candidatos a inibidores farmacológicos da enzima IDO e/ou como protótipos para a síntese de novos inibidores. / Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme via the kynurenine pathway. Increased IDO expression is largely responsible for the immune tolerance response and can be induced by IFN-γ and lipopolysaccharide (LPS). It is known that IDO participates in the mechanism of tumor immune tolerance and have been reported as a tumor progression marker. Thus, to restore the anti-tumor immunity of the host, IDO inhibition has been considered as a strategy for anticancer therapy. N, N-dimethyltryptamine (DMT) and tryptamine (TRY) are endogenous indolic compounds originated from a parallel route of tryptophan metabolism - the tryptamines route, which occurs mainly in the central nervous system. This study aimed to assess whether DMT and TRY modulate the IDO activity. The results showed inhibitory actions for both compounds and enzyme kinetics revealed Ki = 506µM to DMT and Ki = 156µM to TRY, with inhibitory profiles characteristic of classical non-competitive inhibitors. The inhibitory activity was also observed on the IDO constitutively expressed or induced by IFN-γ in A172 human glioblastom cell line. Using the same line, in parallel group study, we evaluated the influence of DMT and TRY on the IDO gene expression. We conclude that in cells the evaluated compounds inhibitory action is exerted directly on its enzymatic activity without reduction of its transcription. The results of this study also served as the basis for studies of DMT and TRY inhibitory activity in A172 cells with human mononuclear cells co-culture system, in which was observed significant reduction in enzyme activity and tumor cells proliferation. In conclusion we show the possibility that the tryptamines route, through its metabolites, may contribute to quinurenines pathway endogenous regulation and that DMT and TRY should be evaluated as IDO pharmacological inhibitors candidates and / or as prototypes to new inhibitors synthesis.

Background: Migraine headache is a chronic pain condition that affects 20% of women of reproductive age, and is often treated with triptans. Triptans are serotonin 1B, 1D, and 1F receptor agonists that act as vasoconstrictors and inhibitors of the trigeminal cervical complex as well as peripheral neurons; they cross the blood brain barrier and placenta, and as such are plausible neurodevelopmental teratogens. No studies have examined risk of neurodevelopmental problems in children with prenatal triptan exposure. This dissertation had three aims: (1) to examine risk of behavioral problems in children using in the presence of time-varying confounding by concomitant medication use; (2) to examine risk of temperamental, motor, and communication disturbances associated with prenatal triptans exposure, adjusting for unmeasured confounding by migraine type and severity; and (3) to examine changes in neurodevelopment over time associated with prenatal triptan exposure. Methods: This dissertation used data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort including more than 100,000 women recruited during their first prenatal ultrasound visit. Aims 1 and 3 used marginal structural models to assess the risk of (1) neurodevelopmental problems at age 36 months (Aim 1), or (2) change in risk of neurodevelopmental problems from 18 to 36 months (Aim 3) associated with prenatal triptan exposure. Aim 2 used propensity matching and calibration to adjust for unmeasured confounding by migraine type, severity, and attitudes towards medication use in pregnancy. Neurodevelopmental outcome measures included the Child Behavior Checklist (CBCL), the Emotionality, Activity, and Temperament Scale (EAS), and the Ages and Stages Questionnaire (ASQ). Exposure to triptans was ascertained by self-report. Results: Prenatal triptan exposure was associated with greater externalizing behavior problems at 18 and 36 months, as well as greater increases in emotionality and activity from 18 to 36 months. We observed no association between triptan exposure and motor skills or communication problems; triptan use during pregnancy was associated with migraine severity but not migraine type, and adjustment for unmeasured migraine characteristics moved effect estimates towards the null. Conclusions: Prenatal triptan exposure is associated with externalizing-type behaviors and temperament in children, while migraine itself is associated with internalizing-type behaviors and temperament. The use of concomitant medications and the severity of the underlying condition both exerted substantial influence on observed effect estimates, and should be considered in any future studies of triptan medication use in pregnancy.

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