Tesis doctoral de Nuria Cirauqui Díaz
Melanin-concentrating hormone (mch) regulates feeding and energy homeostasis through interaction with its receptor, the melanin-concentrating receptor 1 (mchr1), making it a target in the treatment of obesity. most of the published mchr1 antagonists share a key pharmacophore that contains four common parts: an aromatic region attached to a carboxamide/urea core, which in turn is connected via a linker to a basic amine. Based on the pharmacophore, we have designed three novel series of mchr1 antagonists. Thirty nine compounds were synthesized, characterized and then subjected to affinity assays to three receptors: the mchr1, the histamine 3 receptor (hrh3) and the herg (ether-a-go-go related gene) channel. Seventeen of them show an in vitro inhibitory constant (ki) to the mchr1 lower than 500nm. Biological assays to the second receptor where performed to study the selectivity of our compounds compared to other gpcr members, and biological assays to the third receptor were performed in order to study the toxicity of compounds concerning the herg blockade. the new mchr1 antagonists and their affinity data have been used to develop two in silico models, one to the binding to the target receptor and another to the binding to the herg channel, in order to understand the structure-activity relationships. Biological affinity data of the compounds against hrh3 were used to further validate the mchr1 model. Hrh3 shows high similarities to mchr1 within the ligand binding pocket but it lacks three glutamine residues (gln3.36, gln5.42 and gln6.55) that are predicted by our model to be potentially involved in the binding of antagonists to mchr1. results show that the presence in the antagonists of polar groups able to interact with the aforementioned glutamines is important for their activity towards the mchr1 and their selectivity against other gpcr members. In order to decrease the affinity of compounds to the herg channel, the linkers between the basic amine and the hydrophobic scaffolds must be rigid, and must maintain the compound in an elongated conformation that hinders binding in the herg binding cavity. However, those linkers must allow a good binding in the mchr1 receptor. The introduction of a small apolar side chain in the methyl group between the urea and the biphenyl scaffolds, or those methyl groups between the urea and the piperidine, could improve the affinity for the mchr1, whereas would not be tolerated for the herg channel.
Datos académicos de la tesis doctoral «Diseño, síntesis y evaluación biológica y toxicológica de nuevos compuestos como potenciales antagonistas del receptor mchr1 para el tratamiento de la obesidad. construcción de sendos modelos in silico de unión al receptor diana y al canal de potasio herg«
- Título de la tesis: Diseño, síntesis y evaluación biológica y toxicológica de nuevos compuestos como potenciales antagonistas del receptor mchr1 para el tratamiento de la obesidad. construcción de sendos modelos in silico de unión al receptor diana y al canal de potasio herg
- Autor: Nuria Cirauqui Díaz
- Universidad: Navarra
- Fecha de lectura de la tesis: 24/03/2009
Dirección y tribunal
- Director de la tesis
- Ignacio Aldana Moraza
- Tribunal
- Presidente del tribunal: Antonio Monge vega
- Miguel Fernandez braña (vocal)
- víctor Martínez merino (vocal)
- Juan Miguel López del amo (vocal)