RESUMO
This study explores a combination of the concept of enantioselective enzymatic synthesis of ß-chiral amines through transamination with inâ situ product crystallization (ISPC) to overcome product inhibition. Using 2-phenylpropanal as a readily available and easily racemizing substrate of choice, (R)-ß-methylphenethylamine ((R)-2-phenylpropan-1-amine) concentrations of up to 250â mM and enantiomeric excesses of up to 99 % are achieved when using a commercially available transaminase from Ruegeria pomeroyi in a fed-batch based dynamic kinetic resolution reaction on preparative scale. The source of substrate decomposition during the reaction is also investigated and the resulting unwanted byproduct formation is successfully reduced to insignificant levels.
Assuntos
Cristalização , Fenetilaminas , Transaminases , Fenetilaminas/química , Fenetilaminas/síntese química , Cinética , Estereoisomerismo , Transaminases/metabolismo , Transaminases/químicaRESUMO
In this study, ten phenylpropionyl phenylethylamines, including five previously undescribed ones (1a/b, 2a/b, and 3), five known analogues (4-8), and two established phenylpropanoids precursors (9, 10) were isolated from the aerial parts of Chloranthus henryi Hemsl. Their structures, including absolute configurations, were determined by high-resolution mass spectrometry, enantio-separation, electronic circular dichroism calculation, and single crystal diffraction. Compounds 1a and 1b were the first examples of natural hetero-[2 + 2] cycloaddition products between phenylpropionyl phenylethylamine and phenylpropene. The plausible hetero-[2 + 2] biosynthesis pathway was confirmed by a photocatalytic biomimetic synthesis in eight steps, which also led to the production of three other potential natural homo-[2 + 2] adducts (1'a/b, 2', and 3'). Bioactivity screening indicated that these adducts bear medium inhibitory activity on nitric oxide generation, with IC50 values of 6-35 µM in RAW 264.7 macrophages.
Assuntos
Óxido Nítrico , Fenetilaminas , Camundongos , Animais , Células RAW 264.7 , Fenetilaminas/química , Fenetilaminas/isolamento & purificação , Fenetilaminas/farmacologia , Fenetilaminas/síntese química , Óxido Nítrico/biossíntese , Óxido Nítrico/antagonistas & inibidores , Estrutura Molecular , Amaryllidaceae/química , Biomimética , Relação Dose-Resposta a Droga , Relação Estrutura-AtividadeRESUMO
Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.
Assuntos
Fenetilaminas , Agonistas do Receptor 5-HT2 de Serotonina , Relação Estrutura-Atividade , Animais , Humanos , Fenetilaminas/farmacologia , Fenetilaminas/química , Fenetilaminas/síntese química , Administração Oral , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Masculino , Disponibilidade Biológica , Ratos , Camundongos , Ratos Sprague-Dawley , Descoberta de Drogas , Receptores 5-HT2 de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismoRESUMO
Conventional methods employed today for the synthesis of amides often lack of economic and environmental sustainability. Triazine-derived quaternary ammonium salts, e.g., 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)), emerged as promising dehydro-condensation agents for amide synthesis, although suffering of limited stability and high costs. In the present work, a simple protocol for the synthesis of amides mediated by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a tert-amine has been described and data are compared to DMTMM(Cl) and other CDMT-derived quaternary ammonium salts (DMT-Ams(X), X: Cl- or ClO4-). Different tert-amines (Ams) were tested for the synthesis of various DMT-Ams(Cl), but only DMTMM(Cl) could be isolated and employed for dehydro-condensation reactions, while all CDMT/tert-amine systems tested were efficient as dehydro-condensation agents. Interestingly, in best reaction conditions, CDMT and 1,4-dimethylpiperazine gave N-phenethyl benzamide in 93% yield in 15 min, with up to half the amount of tert-amine consumption. The efficiency of CDMT/tert-amine was further compared to more stable triazine quaternary ammonium salts having a perchlorate counter anion (DMT-Ams(ClO4)). Overall CDMT/tert-amine systems appear to be a viable and more economical alternative to most dehydro-condensation agents employed today.
Assuntos
Amidas/síntese química , Ácidos Carboxílicos/química , Triazinas/química , Aminas/química , Benzamidas/síntese química , Técnicas de Química Sintética/métodos , Percloratos/química , Fenetilaminas/síntese química , Piperazinas/química , Compostos de Amônio Quaternário/química , Solventes/químicaRESUMO
New developments in the synthesis, resolution, and synthetic applications of chiral 1-phenylethylamine (α-PEA) reported in the last decade have been reviewed. In particular, improvements in the synthesis of α-PEA and its derivatives and chiral resolution, as well as their applications in the resolution of other compounds, were discussed. α-PEA was used as a chiral auxiliary in the diastereoselective synthesis of medicinal substances and natural products. Chiral ligands with α-PEA moieties were applied in asymmetric reactions, and effective modular chiral organocatalysts were constructed with α-PEA fragments and used in important synthetic reactions.
Assuntos
Fenetilaminas/química , Fenetilaminas/síntese química , Técnicas de Química Sintética , EstereoisomerismoRESUMO
The chemosensory system of any animal relies on a vast array of detectors tuned to distinct chemical cues. Odorant receptors and the ion channels of the TRP family are all uniquely expressed in olfactory tissues in a species-specific manner. Great effort has been made to characterize the molecular and pharmacological properties of these proteins. Nevertheless, most of the natural ligands are highly hydrophobic molecules that are not amenable to controlled delivery. We sought to develop photoreleasable, biologically inactive odorants that could be delivered to the target receptor or ion channel and effectively activated by a short light pulse. Chemically distinct ligands eugenol, benzaldehyde, 2-phenethylamine, ethanethiol, butane-1-thiol, and 2,2-dimethylethane-1-thiol were modified by covalently attaching the photoremovable protecting group (8-cyano-7-hydroxyquinolin-2-yl)methyl (CyHQ). The CyHQ derivatives were shown to release the active odorant upon illumination with 365 and 405 nm light. We characterized their bioactivity by measuring activation of recombinant TRPV1 and TRPA1 ion channels expressed in HEK 293 cells and the electroolfactogram (EOG) response from intact mouse olfactory epithelium (OE). Illumination with 405 nm light was sufficient to robustly activate TRP channels within milliseconds of the light pulse. Photoactivation of channels was superior to activation by conventional bath application of the ligands. Photolysis of the CyHQ-protected odorants efficiently activated an EOG response in a dose-dependent manner with kinetics similar to that evoked by the vaporized odorant amyl acetate (AAc). We conclude that CyHQ-based, photoreleasable odorants can be successfully implemented in chemosensory research.
Assuntos
Benzaldeídos/farmacologia , Eugenol/farmacologia , Hidroxiquinolinas/química , Odorantes , Fenetilaminas/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Benzaldeídos/síntese química , Eugenol/síntese química , Feminino , Células HEK293 , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/efeitos da radiação , Masculino , Camundongos , Mucosa Olfatória/efeitos dos fármacos , Fenetilaminas/síntese química , Compostos de Sulfidrila/síntese química , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Raios UltravioletaRESUMO
Identification of a ligand binding site represents the starting point for a structure-based drug development program. Lack of a binding site hampers the development of improved ligands that modulate the protein of interest. In this letter, we describe the development of chemical tools that will allow for elucidation of the Hsp90 C-terminal ligand binding site. Our strategy is based on the preparation of paramagnetic analogs of KU-596, an investigational new drug that is currently undergoing clinical trials for the treatment of neuropathy and interacts with the Hsp90 C-terminal domain. In particular, we report the design and synthesis of three novel paramagnetic analogs of KU-596, which will be used to obtain long range distances for NMR structural studies of Hsp90 in complex with C-terminal ligands.
Assuntos
Glicosídeos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Fenetilaminas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicosídeos/síntese química , Glicosídeos/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ligantes , Estrutura Molecular , Fenetilaminas/síntese química , Fenetilaminas/química , Relação Estrutura-AtividadeRESUMO
N-(2-Methoxybenzyl)-2,5-dimethoxyphenethylamines (NBOMes) are synthetic phenethylamine derivatives emerging on the global drug market and reported to be associated with untoward effects in people who use drugs. Its action involves agonism at serotonin 5-HT2A receptors, affecting cognitive and behavioral processes. However, certain isomers of NBOMes may not show any psychoactive effects. They are not controlled by legislation and can be tested as pharmaceutical drugs. This study deals with the differentiation among positional isomers of 25H-NBOMe differing in the position of the two methoxy groups in the phenylethyl moiety of the molecule, using chromatography-mass spectrometry methods. The gas chromatography analysis showed that the isothermal mode was more efficient than the usually applied temperature-programming mode for the separation of the mentioned isomers. Electron ionization mass spectra of 25H-NBOMe isomers were highly similar, often resulting in a high probability of erroneous identification. However, mass spectra of their trifluoroacetyl or pentafluoropropanoyl derivatives were easily identified as they contained fragments with many significant differences. The proposed analysis using liquid chromatography-tandem mass spectrometry could distinguish the isomers of 25H-NBOMe without the need for any derivatization.
Assuntos
Cromatografia Líquida/métodos , Alucinógenos/análise , Fenetilaminas/análise , Espectrometria de Massas em Tandem/métodos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Alucinógenos/síntese química , Alucinógenos/química , Isomerismo , Fenetilaminas/síntese química , Fenetilaminas/químicaRESUMO
Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.
Assuntos
Benzofuranos/química , Fenetilaminas/química , Sulfonamidas/química , Triazóis/química , Benzofuranos/síntese química , Catálise , Fenetilaminas/síntese química , Sulfonamidas/síntese químicaRESUMO
We previously reported on a series of small molecules targeting the κ-opioid (KOP) receptor featuring a diphenethylamine scaffold and showed the promise of these ligands as effective analgesics with reduced liability for adverse effects. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds 1 (HS665) and 2 (HS666). A library of new diphenethylamines was designed, synthesized, and pharmacologically evaluated. In comparison with 1 and 2, the KOP receptor affinity, selectivity, and agonist activity were modulated by introducing bulkier N-substituents, a 2-fluoro substitution, and additional hydroxyl groups at positions 3' and 4'. Several analogues showed subnanomolar affinity and excellent KOP receptor selectivity acting as full or partial agonists, and one as an antagonist. The new diphenethylamines displayed antinociceptive efficacies with increased potencies than U50,488, 1 and 2 in the writhing assay and without inducing motor dysfunction after sc administration in mice.
Assuntos
Analgésicos/química , Analgésicos/farmacologia , Fenetilaminas/química , Fenetilaminas/farmacologia , Receptores Opioides kappa/metabolismo , Analgésicos/síntese química , Animais , Células CHO , Cricetulus , Humanos , Masculino , Camundongos , Fenetilaminas/síntese química , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
We have developed a method for palladium-catalyzed, pyrazole-directed sp3 C-H bond arylation by aryl iodides. The reaction employs a Pd(OAc)2 catalyst at 5-10â mol % loading and silver(I) oxide as a halide-removal agent, and it proceeds in acetic acid or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of the pyrazole moiety affords pharmaceutically important ß-phenethylamines.
Assuntos
Paládio/química , Fenetilaminas/síntese química , Pirazóis/química , Catálise , Iodetos/síntese química , Iodetos/química , Óxidos/química , Fenetilaminas/química , Pirazóis/síntese química , Compostos de Prata/químicaRESUMO
Leishmania (Leishmania) infantum chagasi is one of the agents that cause visceral leishmaniasis. This disease occurs more frequently in third world countries, such as Brazil. The treatment is arduous, and is dependent on just a few drugs like the antimonial derivatives and amphotericin B. Moreover, these drugs are not only expensive, but they can also cause severe side effects and require long-term treatment. Therefore, it is very important to find new compounds that are effective against leishmaniasis. In the present work we evaluated a new group of synthetic amides against the promastigote and amastigote forms of L. infantum chagasi. The results showed that one of these amides in particular, presented very effective activity against the promastigotes and amastigotes of L. infantum chagasi at low concentrations and it also presented low toxicity for mammal cells, which makes this synthetic amide a promising drug for combating leishmaniasis.
Assuntos
Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Fenetilaminas/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Brasil , Linhagem Celular , Descoberta de Drogas , Leishmania/efeitos dos fármacos , Leishmania/ultraestrutura , Leishmania infantum/crescimento & desenvolvimento , Leishmania infantum/fisiologia , Leishmania infantum/ultraestrutura , Estágios do Ciclo de Vida/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Fenetilaminas/síntese química , Fenetilaminas/químicaRESUMO
The κ opioid (KOP) receptor crystal structure in an inactive state offers nowadays a valuable platform for inquiry into receptor function. We describe the synthesis, pharmacological evaluation and docking calculations of KOP receptor ligands from the class of diphenethylamines using an active-like structure of the KOP receptor attained by molecular dynamics simulations. The structure-activity relationships derived from computational studies was in accordance with pharmacological activities of targeted diphenethylamines at the KOP receptor established by competition binding and G protein activation in vitro assays. Our analysis identified that agonist binding results in breaking of the Arg156-Thr273 hydrogen bond, which stabilizes the inactive receptor conformation, and a crucial hydrogen bond with His291 is formed. Compounds with a phenolic 4-hydroxy group do not form the hydrogen bond with His291, an important residue for KOP affinity and agonist activity. The size of the N-substituent hosted by the hydrophobic pocket formed by Val108, Ile316 and Tyr320 considerably influences binding and selectivity, with the n-alkyl size limit being five carbon atoms, while bulky substituents turn KOP agonists in antagonists. Thus, combination of experimental and molecular modeling strategies provides an initial framework for understanding the structural features of diphenethylamines that are essential to promote binding affinity and selectivity for the KOP receptor, and may be involved in transduction of the ligand binding event into molecular changes, ultimately leading to receptor activation.
Assuntos
Fenetilaminas/química , Receptores Opioides kappa/agonistas , Animais , Humanos , Modelos Moleculares , Fenetilaminas/síntese química , Fenetilaminas/farmacologia , Relação Estrutura-AtividadeRESUMO
The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT2A/5-HT2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.
Assuntos
Fenetilaminas/farmacologia , Fenetilaminas/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Anisóis/química , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Células HEK293 , Alucinógenos/química , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Fenetilaminas/síntese química , Fenetilaminas/química , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand. METHODS AND RESULTS: Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/µmol. PET studies in Danish landrace pigs revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [(18)F]2 and [(18)F]3 showed very low brain uptake. CONCLUSION: None of the investigated (18)F-labeled Cimbi-36 derivatives [(18)F]1, [(18)F]2 and [(18)F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.
Assuntos
Benzilaminas/síntese química , Benzilaminas/metabolismo , Radioisótopos de Flúor , Fenetilaminas/síntese química , Fenetilaminas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Animais , Benzilaminas/química , Transporte Biológico , Técnicas de Química Sintética , Feminino , Marcação por Isótopo , Ligantes , Fenetilaminas/química , Agonistas do Receptor 5-HT2 de Serotonina/química , SuínosAssuntos
Amidas/síntese química , Ácidos Graxos Monoinsaturados/síntese química , Indóis/síntese química , Fenetilaminas/síntese química , Pirrolidinas/química , Salicilamidas/química , Antibacterianos/síntese química , Antibacterianos/química , Técnicas de Química Sintética , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel synthetic route to stable deuterium labeled ractopamine was disclosed with 6.49% total yield and 97.7% isotopic abundance. Its structure and the isotope-abundance were confirmed according to (1)H-NMR and high-resolution mass spectrometry.
Assuntos
Deutério/química , Fenetilaminas/síntese química , Fenetilaminas/químicaRESUMO
Cholesteryl ester transfer protein (CETP) inhibitors hold promise as new agents against coronary heart disease. Molecular modeling techniques such as 2D-QSAR and 3D-QSAR analysis were applied to establish models to distinguish potent and weak CETP inhibitors. 2D and 3D QSAR models-based a series of diphenylpyridylethanamine (DPPE) derivatives (newly identified as CETP inhibitors) were then performed to elucidate structural and physicochemical requirements for higher CETP inhibitory activity. The linear and spline 2D-QSAR models were developed through multiple linear regression (MLR) and support vector machine (SVM) methods. The best 2D-QSAR model obtained by SVM gave a high predictive ability (R(2)train=0.929, R(2)test=0.826, Q(2)LOO=0.780). Also, the 2D-QSAR models uncovered that SlogP_VSA0, E_sol and Vsurf_DW23 were important features in defining activity. In addition, the best 3D-QSAR model presented higher predictive ability (R(2)train=0.958, R(2)test=0.852, Q(2)LOO=0.734) based on comparative molecular field analysis (CoMFA). Meanwhile, the derived contour maps from 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving CETP inhibitory activity. Consequently, twelve newly designed DPPE derivatives were proposed to be robust and potent CETP inhibitors. Overall, these derived models may help to design novel DPPE derivatives with better CETP inhibitory activity.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Fenetilaminas/farmacologia , Piridinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Fenetilaminas/síntese química , Fenetilaminas/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Sensory screening of a series of naturally occurring N-cinnamoyl derivatives of substituted phenethylamines revealed that rubemamine (9, from Chenopodium album) and rubescenamine (10, from Zanthoxylum rubsecens) elicit strong intrinsic umami taste in water at 50 and 10 ppm, respectively. Sensory tests in glutamate- and nucleotide-containing bases showed that the compounds influence the whole flavor profile of savory formulations. Both rubemamine (9) and rubescenamine (10) at 10-100 ppm dose-dependently positively modulated the umami taste of MSG (0.17-0.22%) up to threefold. Among the investigated amides, only rubemamine (9) and rubescenamine (10) are able to directly activate the TAS1R1-TAS1R3 umami taste receptor. Moreover, both compounds also synergistically modulated the activation of TAS1R1-TAS1R3 by MSG. Most remarkably, rubemamine (9) was able to further positively modulate the IMP-enhanced TAS1R1-TAS1R3 response to MSG â¼ 1.8-fold. Finally, armatamide (11), zanthosinamide (13), and dioxamine (14), which lack intrinsic umami taste in vivo and direct receptor response in vitro, also positively modulated receptor activation by MSG about twofold and the IMP-enhanced MSG-induced TAS1R1-TAS1R3 responses approximately by 50%. In sensory experiments, dioxamine (14) at 25 ppm in combination with 0.17% MSG exhibited a sensory equivalent to 0.37% MSG.
Assuntos
Chenopodium album/química , Aromatizantes/química , Fenetilaminas/química , Extratos Vegetais/química , Glutamato de Sódio/metabolismo , Zanthoxylum/química , Aromatizantes/síntese química , Aromatizantes/metabolismo , Humanos , Estrutura Molecular , Fenetilaminas/síntese química , Fenetilaminas/metabolismo , Extratos Vegetais/síntese química , Extratos Vegetais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , PaladarRESUMO
Lefetamine (N,N-dimethyl-1,2-diphenylethylamine, L-SPA) was marketed as an opioid analgesic in Japan and Italy. After being widely abused, it became a controlled substance. It seems to be a pharmaceutical lead for designer drugs because N-ethyl-1,2-diphenylethylamine (NEDPA) and N-iso-propyl-1,2-diphenylethylamine (NPDPA) were confiscated by the German police. In contrast to these derivatives, metabolism and detectability of lefetamine were not studied yet. Therefore, phase I and II metabolism should be elucidated and correlated to the derivatives. Also the detectability using the authors' standard urine screening approaches (SUSA) needed to be checked. As lefetamine was commercially unavailable, it had to be synthesized first. For metabolism studies, a high dose of lefetamine was administered to rats and the urine samples worked up in different ways. Separation and analysis were achieved by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS). In accordance with NEPDA and NPDPA, the following metabolic steps could be proposed: N-oxidation, N-dealkylation, mono- and bis-hydroxylation of the benzene ring, and hydroxylation of the phenyl ring only after N-dealkylation. The di-hydroxy metabolites were conjugated by methylation of one hydroxy group, and hydroxy metabolites by glucuronidation or sulfation. All initial metabolites could also be detected in human liver preparations. After a therapeutic lefetamine dose, the bis-nor, bis-nor-hydroxy, nor-hydroxy, nor-di-hydroxy metabolites could be detected using the authors' GC-MS SUSA and the nor-hydroxy-glucuronide by the LC-MS(n) SUSA. Thus, an intake of lefetamine should be detectable in human urine assuming similar pharmacokinetics.