RESUMEN
A computational kinetics study of the antioxidant activity of tryptamine toward HO⢠and HOO⢠radicals in water at 298 K has been carried out. Density functional methods have been employed for the quantum chemical calculations, and the conventional transition state theory was used for rate constant evaluation. Different mechanisms have been considered: radical adduct formation (RAF), single electron transfer (SET), and hydrogen atom transfer (HAT). For the reaction of tryptamine with the hydroxyl radical, nearly all channels are diffusion-controlled, and the overall rate constant is very high, 6.29 × 1010 M-1 s-1. The RAF mechanism has a branching ratio of 55%, followed by the HAT mechanism (31%), whereas the SET mechanism accounts just for 13% of the products. The less hindered carbon atom neighboring to the nitrogen of the indole ring seems to be the preferred site for the RAF mechanism, with a branching ratio of 16%. The overall rate constant for the reaction of tryptamine with the HOO⢠radical is 3.71 × 104 M-1 s-1, suggesting that it could be a competitive process with other reactions of hydroperoxyl radicals in biological environments. For this reaction only the HAT mechanism seems viable. Furthermore, only two centers may contribute to the HAT mechanism, the nitrogen atom of the indole ring and a carbon atom of the aminoethyl chain, the former accounting for more than 91% of the total products. Our results suggest that tryptamine could have a noticeable scavenging activity toward radicals, and that this activity is mainly related to the nitrogen atom of the indole ring, thus showing the relevance of their behavior in the study of aminoindoles.
Asunto(s)
Antioxidantes/química , Triptaminas/química , Transporte de Electrón , Hidrógeno/química , Radical Hidroxilo/química , Cinética , Termodinámica , Agua/químicaRESUMEN
Benzoyltryptamine analogues act as neuroprotective and spasmolytic agents on smooth muscles. In this study, we investigated the ability of N-salicyloyltryptamine (STP) to produce vasorelaxation and determined its underlying mechanisms of action. Isolated rat mesenteric arteries with and without functional endothelium were studied in an isometric contraction system in the presence or absence of pharmacological inhibitors. Amperometric experiments were used to measure the nitric oxide (NO) levels in CD31+ cells using flow cytometry. GH3 cells were used to measure Ca2+ currents using the whole cell patch clamp technique. STP caused endothelium-dependent and -independent relaxation in mesenteric rings. The endothelial-dependent relaxations in response to STP were markedly reduced by L-NAME (endothelial NO synthase-eNOS-inhibitor), jHydroxocobalamin (NO scavenger, 30 µM) and ODQ (soluble Guanylyl Cyclase-sGC-inhibitor, 10 µM), but were not affected by the inhibition of the formation of vasoactive prostanoids. These results were reinforced by the increased NO levels observed in the amperometric experiments with freshly dispersed CD31+ cells. The endothelium-independent effect appeared to involve the inhibition of voltage-gated Ca2+ channels, due to the inhibition of the concentration-response Ca2+ curves in depolarizing solution, the increased relaxation in rings that were pre-incubated with high extracellular KCl (80 mM), and the inhibition of macroscopic Ca2+ currents. The present findings show that the activation of the NO/sGC/cGMP pathway and the inhibition of gated-voltage Ca2+ channels are the mechanisms underlying the effect of STP on mesenteric arteries.
Asunto(s)
Señalización del Calcio/efectos de los fármacos , Endotelio Vascular/metabolismo , Arterias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Salicilatos/farmacología , Guanilil Ciclasa Soluble/metabolismo , Triptaminas/farmacología , Vasodilatación/efectos de los fármacos , Animales , Masculino , Ratas , Ratas Wistar , Salicilatos/química , Triptaminas/químicaRESUMEN
Phytochemical investigation of the alkaloid extract of Palicourea sessilis by LC-HRMS/MS using molecular networking and an in silico MS/MS fragmentation approach suggested the presence of several new monoterpene indole alkaloids. These compounds were isolated by semipreparative HPLC, and their structures confirmed by means of HRMS, NMR, and ECD measurements as 4-N-methyllyaloside (3), 4-N-methyl-3,4-dehydrostrictosidine (4), 4ß-hydroxyisodolichantoside (6), and 4α-hydroxyisodolichantoside (7), as well as the known alkaloids alline (1), N-methyltryptamine (2), isodolichantoside (5), and 5-oxodolichantoside (8). In addition, the acetylcholinesterase inhibitory activity of the compounds was evaluated up to 50 µM.
Asunto(s)
Inhibidores de la Colinesterasa/aislamiento & purificación , Rubiaceae/química , Alcaloides de Triptamina Secologanina/aislamiento & purificación , Acetilcolinesterasa/efectos de los fármacos , Brasil , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Hojas de la Planta/química , Alcaloides de Triptamina Secologanina/química , Triptaminas/químicaRESUMEN
We report 14 harmala and tryptamine-iridoid alkaloids with various tri-, tetra- and pentacyclic cores from leaves and stem bark of six species of the large and complex neotropical genus Palicourea. Among them is the previously undescribed compound deoxostrictosamide which is related to strictosamide, a key intermediate in camptothecin biosynthesis. In addition, we describe the occurrence of 1,2,3,4-tetrahydronorharman-1-one for the first time within Rubiaceae and ophiorine A and B, two alkaloids with an unusual core bearing a betaine function and a zwitterion as new for the genus. Although the other compounds are already known from other species, their degree of structural diversity highlights the remarkable biosynthetic capabilities of the genus Palicourea. Furthermore, the present paper provides additional support for the hypothesis that tryptamine-iridoid alkaloids represent a distinct chemosystematic feature for the genus Palicourea.
Asunto(s)
Rubiaceae/química , Triptaminas/química , Alcaloides/análisis , Alcaloides/química , Biodiversidad , Camptotecina , Costa Rica , Iridoides/análisis , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/química , Hojas de la Planta/química , Alcaloides de la Vinca/químicaRESUMEN
For the treatment of chronic ocular diseases such as glaucoma, continuous instillations of eye drops are needed. However, frequent administrations of hypotensive topical formulations can produce adverse ocular surface effects due to the active substance or other components of the formulation, such as preservatives or other excipients. Thus the development of unpreserved formulations that are well tolerated after frequent instillations is an important challenge to improve ophthalmic chronic topical therapies. Furthermore, several components can improve the properties of the formulation in terms of efficacy. In order to achieve the mentioned objectives, we have developed formulations of liposomes (150-200 nm) containing components similar to those in the tear film and loaded with the hypotensive melatonin analog 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT, 100 µM). These formulations were combined with mucoadhesive (sodium hyaluronate or carboxymethylcellulose) or amphiphilic block thermosensitive (poloxamer) polymers to prolong the hypotensive efficacy of the drug. In rabbit eyes, the decrease of intraocular pressure with 5-MCA-NAT-loaded liposomes that were dispersed with 0.2% sodium hyaluronate, 39.1±2.2%, was remarkably higher compared to other liposomes formulated without or with other bioadhesive polymers, and the effect lasted more than 8 hours. According to the results obtained in the present work, these technological strategies could provide an improved modality for delivering therapeutic agents in patients with glaucoma.
Asunto(s)
Adhesivos/química , Química Farmacéutica/métodos , Liposomas/química , Melatonina/análogos & derivados , Polímeros/química , Triptaminas/química , Triptaminas/farmacología , Animales , Antihipertensivos/efectos adversos , Antihipertensivos/química , Antihipertensivos/farmacología , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Presión Intraocular/efectos de los fármacos , Masculino , Concentración Osmolar , Tamaño de la Partícula , Conejos , Lágrimas/química , Lágrimas/efectos de los fármacos , Triptaminas/efectos adversos , ViscosidadRESUMEN
In this work, we report a molecular dynamics simulations study of protonated triptans, sumatriptan and naratriptan, in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC). The simulations were carried out at two concentrations for each drug. Our results show partition between the lipid head-water interphase and water phase for both triptans, with increasing access to the water phase with increasing concentrations. The triptans were stabilized at the interphase through different specific interactions with the POPC bilayer such as hydrogen bonds, salt bridges, and cation-π. Besides, sumatriptan and naratriptan protonated molecules have no access to the hydrophobic region of the bilayer at the studied conditions. Similar results were found for both drugs, however protonated naratriptan shows slightly higher affinity for the water phase. This behavior was attributed to the bulky lateral amino group in its structure under the studied conditions (drugs were originally placed at the water phase). This work represents a first insight to the comprehensive understanding of triptan partition in model membranes.
Asunto(s)
Membrana Dobles de Lípidos , Simulación de Dinámica Molecular , Fosfatidilcolinas/química , Piperidinas/química , Sumatriptán/química , Triptaminas/química , Estabilidad de Medicamentos , Enlace de Hidrógeno , Estructura Molecular , Protones , Solubilidad , Relación Estructura-Actividad , Agua/químicaRESUMEN
The TRA (3-[2-aminoethyl]indole) is an important neurotransmitter with a close structural and chemical similarity to the neurotransmitter serotonin (5-hydroxytryptamine), and to melatonin (5-methoxy-N-acetyltryptamine), which plays a key role in daily human behavior. Moreover, TRA, and other indolic compounds are very efficient antioxidants. In this work the conformational space of TRA was scanned in aqueous solution, simulating the solvent by the polarizable continuum model. Geometry optimizations were performed at B3LYP/6-31+G** level. Electronic distributions were analyzed at a better calculation level, thus improving the basis set (6-311++G**). A topological study based on Bader's theory (atoms in molecules) and natural bond orbital (NBO) framework was performed. Structural changes found in solution were related with charge delocalization mechanisms, which explained the changes in the conformational relative population in aqueous phase. Solvent effects on molecular electrostatic potential (MEPs) were also quantified and rationalized through charge delocalization mechanisms, thus connecting changes in MEPs with changes in structure, bond polarization, orbital bonding populations, natural charges, and bond topological properties. Moreover, polarizabilities and dipolar moments were calculated. All conformers were taken into account. Our results are the first prediction of TRA polarizabilities. The results reported contribute to the understanding of the structure, stability and reactivity of TRA and other indole derivatives.
Asunto(s)
Triptaminas/química , Agua/química , Antioxidantes/química , Humanos , Enlace de Hidrógeno , Melatonina/química , Modelos Moleculares , Conformación Molecular , Neurotransmisores/química , Neurotransmisores/metabolismo , Serotonina/química , Soluciones , Solventes , Electricidad Estática , TermodinámicaRESUMEN
UNLABELLED: Due to the free radical scavenger properties of Tryptamine (TRA), as well as of others indole derivatives, it is in our interest to explore deeply the stereoelectronic aspects that would be relevant in their stabilization and antioxidant activity. In this work the conformational space of TRA was scanned using molecular dynamics complemented with functional density calculations at B3LYP/6-31 + G** level. Twenty one conformers of lowest energy were obtained, their electronic distributions were analyzed at a higher calculation level, thus improving the basis set (B3LYP/6-311++G**). A topological study based on Bader's theory ( AIM: atoms in molecules) and natural bond orbital (NBO) framework was performed. The study was enriched by a deep analysis of maps of molecular electrostatic potential (MEP) through a coordinated NBO/AIM analysis. The conformational preferences were explained by hyperconjugative interactions, which were revealed by NBO data. Because radical scavenging by indolic compounds is strongly modulated by their functional residues our study was related to similar analysis done previously on Indole and 1H-indole-3-acetic acid (IAA). Therefore, the conformational space of TRA was studied from a new perspective focusing on a deep analysis of the geometric and electronic properties of TRA conformers. The changes of the electronic distribution introduced by the substituent and the conformational flexibility of the side chain were addressed. The results reported contribute to the understanding of the structure, stability and reactivity of TRA and others indole derivatives.
Asunto(s)
Depuradores de Radicales Libres/química , Simulación de Dinámica Molecular , Triptaminas/química , Algoritmos , Enlace de Hidrógeno , Conformación Molecular , Teoría Cuántica , Propiedades de Superficie , TermodinámicaRESUMEN
We investigated the antinociceptive and nerve excitability effects of the N-salicyloyltryptamine (NST) NST-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg (i.p.) were administered (i.p.). This effect was not antagonized by naloxone (1.5 mg/kg, i.p.). NST inhibited the licking response of the injected paw when 100 and 200 mg/kg were administered (i.p.) to mice in the first and second phases of the formalin test. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and showed that NST (3.57 mM) significantly reduced (29.2%) amplitude of the compound action potential (CAP) suggesting a sodium channel effect induced by NST. Our results demonstrated an antinociceptive activity of the NST that could be, at least in part, associated to the reduction of the action potential amplitude. NST might represent an important tool for pain management.
Asunto(s)
Analgésicos/farmacología , Conducta Animal/efectos de los fármacos , Bioensayo/métodos , Fenómenos Electrofisiológicos/efectos de los fármacos , Salicilatos/farmacología , Triptaminas/farmacología , Ácido Acético , Potenciales de Acción/efectos de los fármacos , Analgésicos/uso terapéutico , Animales , Diazepam/uso terapéutico , Formaldehído , Indometacina/farmacología , Masculino , Ratones , Dolor/tratamiento farmacológico , Prueba de Desempeño de Rotación con Aceleración Constante , Salicilatos/química , Salicilatos/uso terapéutico , Factores de Tiempo , Triptaminas/química , Triptaminas/uso terapéuticoRESUMEN
The electrochemical behavior and the analytical application of the selective serotonin agonist naratriptan (N-methyl-3-(1-methyl-4-piperidyl)indole-5-ethanesulfonamide) are presented herein. Naratriptan exhibits an anodic response in aqueous media over a broad pH range (pH 2-12), as determined by differential pulse voltammetry and cyclic voltammetry using glassy carbon electrodes. This response is irreversible in nature, diffusion-controlled and probably caused by the oxidation of the naratriptan indole moiety. The differential pulse voltammetry technique was performed in 0.1 mol L(-1) Britton-Robinson buffer (pH=3), which elicited the most reproducible results. The percentage of naratriptan recovery was 102.1+/-1.8%, and the limits of detection and quantitation were 9.5x10(-6) and 2.0x10(-5) mol L(-1), respectively. Selectivity trials revealed that the oxidation signal of the drug was not disturbed by the presence of excipients or degradation products. Thus, we conclude that the method presented herein is useful for the quantification of naratriptan in pharmaceutical drugs and that this method requires no separations or extractions. Finally, this voltammetric method was successfully applied to determine the quantity and the content uniformity of naratriptan in drug tablets. A comparison of this technique to the standard high-performance liquid chromatography technique was conducted at the end of our study.
Asunto(s)
Piperidinas/análisis , Comprimidos/química , Triptaminas/análisis , Carbono/química , Cromatografía Líquida de Alta Presión , Electroquímica/métodos , Electrodos , Vidrio/química , Estructura Molecular , Piperidinas/química , Agonistas de Receptores de Serotonina/análisis , Triptaminas/químicaRESUMEN
A direct injection/liquid chromatography-electrospray ionization-tandem mass spectrometry procedure has been developed for the simultaneous quantitation of 11 compounds potentially found in the increasingly popular Amazonian botanical medicine and religious sacrament ayahuasca. The method utilizes a deuterated internal standard for quantitation and affords rapid detection of the alkaloids by a simple dilution assay, requiring no extraction procedures. Further, the method demonstrates a high degree of specificity for the compounds in question, as well as low limits of detection and quantitation despite using samples for analysis that had been diluted up to 200:1. This approach also appears to eliminate potential matrix effects. Method bias for each compound, examined over a range of concentrations, was also determined as was inter- and intra-assay variation. Its application to the analysis of three different ayahuasca preparations is also described. This method should prove useful in the study of ayahuasca in clinical and ethnobotanical research as well as in forensic examinations of ayahuasca preparations.
Asunto(s)
Alcaloides/análisis , Banisteriopsis/química , Cromatografía Liquida/métodos , Plantas Medicinales/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Triptaminas/análisis , Alcaloides/química , Brasil , Peso Molecular , Psicotrópicos/análisis , Psicotrópicos/química , Estándares de Referencia , Reproducibilidad de los Resultados , Factores de Tiempo , Triptaminas/químicaRESUMEN
OBJECTIVE: To study the effect of various triptan-like drugs, eg, avitriptan, naratriptan, and sumatriptan, as well as the benzopyran alnitidan, on the natural killer cell (NKC) activity of peripheral blood mononuclear cell (PBMC) samples and highly purified NKC (HPNKC) preparations. We also examined the possible role of these agents as immunomodulators by studying their effect upon the in vitro secretion of pro-matrix metalloproteinase-9 (pMMP-9) from whole blood and purified neutrophils samples. BACKGROUND: The pharmacological profile of a large number of triptan-like compounds has been extensively studied. However, relatively little is known of their interactions with cellular components of the immune system. METHODS: Blood was obtained from nonsmoking, drug-free healthy individuals from the Blood Bank of the University of Chile main Clinical Hospital (J.J.A.). PBMC were separated by centrifugation and HPNKC acquired by an immunomagnetic isolation procedure. NKC cytotoxicity was assayed using (51)Cr-labeled K-562 cells as target. Addition of drugs and of effector cells (30 : 1, 50 : 1, and 70 : 1 ratio for PBMCs, and 5 : 1 for HPNKCs) was followed by incubation. Paired Student's t-test (2-tailed) was used to determine the significance of the specific (51)Cr release in controls vs drug-treated samples. Aliquots of whole blood or purified neutrophils were added test drug, incubated, centrifuged, and the supernatant analyzed by gelatine zymography. Gelatinolytic activity was visualized, and a digested zone at MW 92 kD indicated presence of pMMP-9. Area of proteolysis was estimated by densitometry; prestained standards were used to assess pMMP-9 molecular weight. RESULTS: Peripheral blood mononuclear cell's NKC cytotoxicity was consistently decreased after incubation with each and every one of the drugs tested. This result, observed for the 3 effector : target (E : T) cell ratios used, was relatively similar among the various compounds studied, and reached statistical significance only at E : T 70 : 1. Similar drug treatment failed, however, to produce significant changes in the cytotoxicity of HPNKC preparations, suggesting that modulation of the PBMC's NKC activity and that of HPNKC samples require different kinds of cell's derived signal. Incubation with either of the drugs tested failed to significantly alter (basal) nonstimulated pMPP-9 secretion by whole blood samples. However, basal pMMP-9 secretion by purified neutrophil preparations was significantly inhibited by alnitidan and sumatriptan, and not affected by naratriptan. CONCLUSIONS: Various drugs with a triptan-like chemical structure interact with cellular components of the innate immune system, resulting in an apparent indirect inhibition of NKC activity and direct inhibition of neutrophils pMMP-9 secretion. These results suggest that they may play a positive role in decreasing the severity of inflammatory processes. Whether this effect is part of triptans antimigraine mechanism of action, or just an added beneficial effect of their use for the reversal treatment of migraine headaches remains to be explored.
Asunto(s)
Pruebas Inmunológicas de Citotoxicidad , Factores Inmunológicos/farmacología , Células Asesinas Naturales/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Triptaminas/farmacología , Adulto , Benzopiranos/química , Benzopiranos/farmacología , Biomarcadores/análisis , Biomarcadores/sangre , Células Cultivadas , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Factores Inmunológicos/química , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Estructura Molecular , Neutrófilos/inmunología , Piperidinas/química , Piperidinas/farmacología , Sumatriptán/química , Sumatriptán/farmacología , Triptaminas/químicaRESUMEN
Chemical studies of a Bacillus endophyticus isolated from a Bahamian hypersaline microbial mat led to the isolation of bacillamides B and C, new tryptamide thiazole metabolites. Bioassay-guided fractionation using a HPLC-UV-MS bioassay technique enabled the detection of these trace fermentation products, and their total structures were elucidated by combined spectroscopic techniques.
Asunto(s)
Bacillus/química , Tiazoles/aislamiento & purificación , Triptaminas/aislamiento & purificación , Microbiología del Agua , Bahamas , Cromatografía Líquida de Alta Presión , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Tiazoles/química , Triptaminas/químicaRESUMEN
The prevalence of migraine is high, affecting a significant proportion of the adult population during their most productive years of life and promoting impairment of their normal daily activities. Although guidelines for the acute treatment of migraine are available, outcome parameters are sometimes still below the expectations of both patients and physicians. Triptans represented an advance in clinical practice and have become the most well-studied class of medication for migraine. These agents present class I evidence for efficacy. However, they differ with regard to several of their clinical parameters, including onset of relief and consistency of response. Rizatriptan is a selective agonist of the 5-hydroxytryptophan(1B/1D )receptors, with proven superiority over placebo, ergotamine and selected oral triptans, demonstrating a good profile of safety and tolerability.
Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Agonistas de Receptores de Serotonina/uso terapéutico , Triazoles/uso terapéutico , Triptaminas/uso terapéutico , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Testimonio de Experto , Humanos , Metaanálisis como Asunto , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Triazoles/química , Triazoles/metabolismo , Triazoles/farmacología , Triptaminas/química , Triptaminas/metabolismo , Triptaminas/farmacologíaRESUMEN
A series of derivatives analogous to Nb-benzoyltryptamine were synthesized by the Schotten-Bauman procedure. The products obtained were: Nb-4-methoxy-benzoyltryptamine, Nb-2,4-dimethoxy-benzoyltryptamine, Nb-3,4-dimethoxy-benzoyltryptamine, Nb-3,4-methylenedioxy-benzoyltryptamine and Nb-3,4,5-trimethoxy-benzoyltryptamine. They were characterized through the usual spectrometric methods (UV, IR, 1H and 13C NMR) and showed non-selective relaxant activity in guinea-pig ileum pre-contracted with acetylcholine, histamine and KCl.
Asunto(s)
Íleon/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Triptaminas/farmacología , Acetilcolina/farmacología , Animales , Estimulación Eléctrica , Cobayas , Histamina/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Íleon/fisiología , Técnicas In Vitro , Espectroscopía de Resonancia Magnética/métodos , Músculo Liso/fisiología , Cloruro de Potasio/farmacología , Espectrofotometría/métodos , Relación Estructura-Actividad , Triptaminas/síntesis química , Triptaminas/químicaRESUMEN
A new tryptamine analogue, N-salicyloyltryptamine (STP), a potential central nervous system (CNS) depressant, was tested in the pentylenetetrazol (PTZ) and maximal electroshock (MES) models of epilepsy in mice. When administered concurrently, STP (100 mg/kg ip) significantly reduced the number of animals that exhibited PTZ-induced seizures and eliminated the extensor reflex of maximal electric-induced seizures test in 50% of the experimental animals. In addition, it showed protection in the PTZ test by diminishing the death rate.