RESUMEN
Diarrhea is one of the most important causes of mortality in the developing world, being responsible for 2.5 million deaths each year. Many of these deaths are caused by enterotoxigenic strains of bacteria, like Escherichia coli, that produce enterotoxins that cause acute watery diarrhea, commonly defined as secretory diarrhea. Studies on symptomatic patients indicate a high prevalence of enterotoxigenic E. coli strains producing the heat-stable toxin, STa. STa is a small, cysteine-rich peptide that binds to the extracellular receptor domain of guanylyl cyclase C (GCC), located at the luminal membrane of intestinal epithelial cells. GCC and its endogenous peptide ligands, guanylin and uroguanylin, play a key role in balancing water absorption and hydration of the intestinal lumen, as exemplified by the finding that loss of GCC function causes severe dehydration of the intestinal lumen, culminating in intestinal obstruction. From a mechanistic viewpoint, reduction of GCC activity offers an efficient approach to limit enterotoxigenic E. coli- provoked secretory diarrhea. Inhibition of GCC-mediated cGMP production would not only reduce anion secretion, but would also restore NHE3 activity, resulting in a comprehensive antidiarrheal action. In the present study, two novel phenylpyrimidinone derivatives were simultaneously synthesized and tested for their ability to block STa-induced CFTR activity in T84 cells.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Inhibidores Enzimáticos/farmacología , Pirimidinonas/farmacología , Receptores de Enterotoxina/antagonistas & inhibidores , Toxinas Bacterianas/metabolismo , Línea Celular , Diarrea/microbiología , Diarrea/prevención & control , Enterotoxinas/metabolismo , Enterotoxinas/toxicidad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Proteínas de Escherichia coli/metabolismo , Hormonas Gastrointestinales/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Péptidos Natriuréticos/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/química , Receptores de Enterotoxina/metabolismoRESUMEN
The synthesis of non natural amino acid 2-amino-3,3,4-trimethyl-pentanoic acid (Ipv) ready for solid phase peptide synthesis has been developed. Copper (I) chloride Michael addition, followed by a Curtius rearrangement are the key steps for the lpv synthesis. The racemic valine/leucine chimeric amino acid was then successfully inserted in position 5 of neuropeptide S (NPS) and the diastereomeric mixture separated by reverse phase HPLC. The two diastereomeric NPS derivatives were tested for intracellular calcium mobilization using HEK293 cells stably expressing the mouse NPS receptor where they behaved as partial agonist and pure antagonist.
Asunto(s)
Leucina/química , Ácidos Pentanoicos/química , Péptidos/síntesis química , Valina/química , Animales , Calcio/metabolismo , Cromatografía Líquida de Alta Presión , Cobre , Células HEK293 , Humanos , Indicadores y Reactivos , Ratones , Técnicas de Síntesis en Fase Sólida , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of 4-substituted piperazine derivatives bearing a norbornene nucleus have been prepared and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compounds showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (alpha1 and alpha2) receptors. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on serotonin receptors and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in nanomolar range towards 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, alpha1 and alpha2). Compound 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (Ki = 1.13 nM), was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compound 3p showed mixed 5-HT2A/5-HT2C activity with affinity values in nanomolar range.
Asunto(s)
Norbornanos/síntesis química , Norbornanos/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Serotoninérgicos/síntesis química , Serotoninérgicos/farmacología , Animales , Química Encefálica/efectos de los fármacos , Ligandos , Espectroscopía de Resonancia Magnética , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/química , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2C/química , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Dopamina D1/química , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismoRESUMEN
Several studies have been published on discovering involvement of PARs receptors in a number of disease states, including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. This mini-review will focus on recent advances in the synthesis of PAR ligands highlighting their therapeutic potential in the treatment of various inflammatory diseases.
Asunto(s)
Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Compuestos Orgánicos/síntesis química , Compuestos Orgánicos/farmacología , Receptores Proteinasa-Activados/agonistas , Receptores Proteinasa-Activados/antagonistas & inhibidores , Animales , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Materiales Biomiméticos/uso terapéutico , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Humanos , Ligandos , Compuestos Orgánicos/química , Compuestos Orgánicos/uso terapéutico , Receptores Proteinasa-Activados/metabolismoRESUMEN
The interest in the microwave assisted organic synthesis has been growing during the recent years. It results from an increasing knowledge of fundamentals of the dielectric heating theory, availability of an equipment designed especially for the laboratory use as well as the discovery of the special techniques of the microwave syntheses. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry and this aspect is of great importance in high-speed combinatorial and medicinal chemistry. In this contribution, the current state of the art is summarized providing examples of the most recent applications in the field of microwave assisted synthesis of biologically active compounds both in heterocyclic and in peptide and peptidomimetic optimization.
Asunto(s)
Descubrimiento de Drogas/métodos , Microondas , Química Farmacéutica/métodos , Técnicas Químicas Combinatorias/métodos , Descubrimiento de Drogas/instrumentación , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Modelos Químicos , Estructura Molecular , Péptidos/síntesis química , Péptidos/químicaRESUMEN
Galanthamine is an alkaloid approved for the treatment of Alzheimer's disease. In this paper the syntheses and the anticholinesterase activities of new glucosyl and nitroxy derivatives substituted on position 6 are reported. Compounds 2, 3 and 5 presented a percentage of inhibition of 35.22%, 47.48% and 67.89% respectively.