New quinoxaline and indole derivatives as MT1 and MT2 receptor agonists
Autor(es) : 
Palabras clave : 
Materias Investigacion::Química::Química orgánica
Materias Investigacion::Farmacia::Química farmacéutica
KNN maps
Molecular modeling
Organic synthesis
Sleep disorders
Indole
Quinoxaline
Fecha de publicación: 
2014
Fecha de la defensa: 
20-abr-2012
Editorial : 
Servicio de Publicaciones de la Universidad de Navarra
Cita: 
ANCIZU PEREZ DE CIRIZA, Saioa. “New quinoxaline and indole derivatives as MT1 and MT2 receptor agonists”. Galiano Ruiz, Silvia (dir.) y Aldana Moraza, Ignacio (codir.). Tesis doctoral. Universidad de Navarra, Pamplona, 2012
Resumen
There is a vast amount of studies which state that sleep is necessary for many functions, such as for encoding and consolidation of memory, for regulation of cognitive and emotional brain processes, for saving energy, for removing free radicals and for regulation of some neurotransmitters. Sleep disorders include a very frequent pathology of diverse origins. These disorders can appear alone or associated with each other, thereby making this pathology even more complex. In the second international classification of sleep disorders (ICSD-2), more than 90 sleep disorders are included divided in eight main categories. The most common sleep disorders include insomnia, sleep apnea, restless legs syndrome, and narcolepsy, with insomnia being the most prevalent among them. The treatment of insomnia for example, involves a great variety of treatments including psychological and behavioral therapies as well as pharmacological therapies. In many cases, combining the behavioral and pharmacological strategies results in the most efficacious treatment. In the past few years, melatonin receptors MT1 and MT2 have become one of the most interesting pharmacological targets for the treatment of many sleep disorders. Ever since the idea arose with regard to melatonin (MLT) acting as a hormonal photoperiodic messenger controlling the biological ¿clocks¿ of the individuals, the hypothesis that MLT administration might be a potential therapy to treat sleep disorders gained more acceptance. MLT exerts too many effects in the body including initiation and maintenance of sleep by the activation of MLT receptors MT1 and MT2. In the last few decades, a multitude of research groups have centered their efforts on the obtainment of new MT1 and MT2 receptor agonists in order to find a new drug for the treatment of diverse sleep disorders. All those compounds contain, without exception, an aliphatic chain substituted on a central aromatic ring and linked to an alkylamide or a derivative. Moreover, in the majority of these cases, the structures also possess an alkoxy group, generally a methoxy, joined to the central core. The principal aim of this work has been to synthesize new molecules as agonists of the melatonin receptors MT1 and MT2 with potential activity for the treatment of sleep disorders. In this sense, after having carried out an extensive bibliographical review, some initial compounds have been designed. Later, after obtaining the biological activity values, a SAR study has been performed and the starting hypothesis has been then redefined, followed by optimization of the initially designed structures. In addition, when enough data has been collected, alternative molecular modeling techniques have been included in this cycle that allows the discrimination of inactive molecules in stages previous to their synthesis. During this project forty-eight final compounds have been synthesized, for which four different synthetic routes have been optimized. Once the new derivatives have been chemically characterized, they have been sent to the ¿Institute de Recherches Servier¿ in France for being biologically evaluated in order to know their affinity for MT1/MT2 receptors first and their agonism/antagonism profile then. With this data a SAR study have been carried out which in combination with new bibliographic reviews performed have permit the redefinition of the starting hypothesis as well as of the initially designed structures. All these approaches have provided significantly promising results that open a new line of research for the development of future MT1/MT2 receptor agonists.

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Fichero: 
TesisDoctoral_SaioaAncizu.pdf
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7,57 MB
Formato: 
Adobe PDF


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