Publication: Allosteric modulators of serotonin and dopamine receptors: new drugs on GPCRs
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2018-09-04
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Universidad Complutense de Madrid
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Abstract
Los receptores acoplados a proteínas G son proteínas de membrana presentes en las células eucariotas, cuya estimulación extracelular se traduce en respuestas funcionales dentro de la célula. En función de su secuencia primaria, se pueden clasificar en cuatro clases diferentes: clase A o familia de la rodopsina, clase B o familia de la secretina, clase C o familia del glutamato y clase F o familia Frizzled.1,2 La activación de estos receptores tras la unión de un ligando en la zona extracelular induce cambios conformacionales que permiten al receptor interaccionar con la proteína G adecuada, la cual desencadena una serie de vías de señalización a través de segundos mensajeros. En algunos casos, las -arrestinas pueden actuar como vía de señalización alternativa e independiente.3 Los receptores acoplados a proteínas G suponen el grupo más grande de receptores de membrana codificados por el genoma humano (~2%)4 y están asociados a una gran diversidad de enfermedades, lo que les convierte en dianas terapéuticas de multitud de programas de descubrimiento de fármacos. Tradicionalmente, el desarrollo de fármacos que actúan sobre estos receptores se ha centrado en encontrar agonistas o antagonistas que desplazan al ligando endógeno activando o bloqueando el receptor.5 Durante las dos últimas décadas, han aparecido nuevas estrategias como por ejemplo el desarrollo de ligandos biased,6 bitópicos,7 moduladores alostéricos,8,9 pepducinas10 o ligandos dirigidos a heterómeros de receptores acoplados a proteínas G (Figura 1).11 Algunas de estas metodologías han dado lugar a moléculas que se encuentran actualmente en ensayos clínicos o incluso comercializadas...
G protein-coupled receptors (GPCRs) are eukaryotic cell membrane proteins that transduce a wide range of extracellular stimuli into intracellular changes in cell function. Based on their amino acid sequence, they can be classified in four different classes: class A or rhodopsin-like family, class B or secretin-like family, class C or glutamate-like family, and class F or Frizzled receptor-like family.1,2 Activation of GPCRs upon ligand binding in the extracellular side triggers conformational changes that allow the receptor to interact with the corresponding heterotrimeric G protein, which initiates a series of downstream signalling pathways via second messenger molecules. Alternatively, -arrestins can act as signalling scaffolds for many GPCR pathways.3 GPCRs represent the largest group of cell surface receptors encoded by the human genome (~2%)4 and have been associated to a multitude of human disorders, which makes them the focus of attention of many drug discovery programs. Traditionally, the development of drugs that target GPCRs has been focused on finding agonists or antagonists that displace the natural or endogenous ligand to activate or inhibit the receptor. Emerging knowledge of structure and physiological functions of GPCRs has begun to alter the approaches to drug discovery.5 Thus, over the past two decades, novel strategies such as the development of biased6 and bitopic ligands,7 allosteric modulators,8,9 pepducins10 or ligands targeting GPCR heteromers11 have appeared (Figure 1). Some of these new approaches have proved to be productive, yielding molecules currently in clinical trials or even marketed. Specifically, allosteric modulators present several advantages in their mechanism of action over “classical” orthosteric ligands, allowing a higher efficacy and selectivity...
G protein-coupled receptors (GPCRs) are eukaryotic cell membrane proteins that transduce a wide range of extracellular stimuli into intracellular changes in cell function. Based on their amino acid sequence, they can be classified in four different classes: class A or rhodopsin-like family, class B or secretin-like family, class C or glutamate-like family, and class F or Frizzled receptor-like family.1,2 Activation of GPCRs upon ligand binding in the extracellular side triggers conformational changes that allow the receptor to interact with the corresponding heterotrimeric G protein, which initiates a series of downstream signalling pathways via second messenger molecules. Alternatively, -arrestins can act as signalling scaffolds for many GPCR pathways.3 GPCRs represent the largest group of cell surface receptors encoded by the human genome (~2%)4 and have been associated to a multitude of human disorders, which makes them the focus of attention of many drug discovery programs. Traditionally, the development of drugs that target GPCRs has been focused on finding agonists or antagonists that displace the natural or endogenous ligand to activate or inhibit the receptor. Emerging knowledge of structure and physiological functions of GPCRs has begun to alter the approaches to drug discovery.5 Thus, over the past two decades, novel strategies such as the development of biased6 and bitopic ligands,7 allosteric modulators,8,9 pepducins10 or ligands targeting GPCR heteromers11 have appeared (Figure 1). Some of these new approaches have proved to be productive, yielding molecules currently in clinical trials or even marketed. Specifically, allosteric modulators present several advantages in their mechanism of action over “classical” orthosteric ligands, allowing a higher efficacy and selectivity...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica I, leída el 27-04-2017