Résumés disponibles (85) :

DUROUX Romain (INSERM U1172 éq. 06 - Said YOUS)
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@mail :  said.yous@univ-lille2.fr      tél. :  03-20-96-43-75


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Titre de la communication :
From design to pharmacological evaluation of benzoxazole derivatives as adenosine A2A receptor antagonists for the potential treatment of Alzheimer disease.
Auteurs (et leurs adresses) de la communication :
Romain Duroux, Laurence Agouridas, Patricia Melnyk, Saïd Yous Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France
Résumé de la communication :
Alzheimer's disease (AD) is the most prevalent form of dementia in the aged population characterized mainly by the presence of senile plaques and neurofibrillary. So far, there is no way to halt or slow-down AD. There is thus a constant need of developing novel therapeutic strategies.
The adenosine A2A receptor (A2AR), expressed in the CNS, belongs to the class of G protein coupled receptor (GPCRs). In recent years, A2AR has attracted growing interest on AD, where it has been proved that A2A receptor is over expressed. It has also been found that A2A receptor antagonists such as caffeine improves memory performance. Though several A2AR antagonists have reached clinical trials, most of them suffer from poor pharmacokinetic and pharmacodynamic properties. Current efforts therefore focus on developing new antagonists with relevant ADME properties.
Based on the recently published crystalline structure of the A2AR complexed with the selective and high-affinity antagonist triazine and on a pharmacophoric model, we designed new ligands using in silico docking studies. Our objective is to develop selective A2AR antagonists devoid of chemical stability, bioavailability and toxicity drawbacks of compounds currently under clinical trials. Pharmacomodulations of a new benzoxazoles family have been developed and show micromolar to nanomolar affinity on HEK293 cells membranes expressing A2AR. Cytotoxicity has also been evaluated on SY5Y cells.
From selected compounds, we evaluated the impact on synaptic transmission by performing hippocampal field excitatory post-synaptic potential recordings (fEPSP) in transgenic rats with a neuronal-specific human A2AR overexpression [tg(CAMKII-hA2AR)] .

DUROUX Romain (INSERM U1172 éq. 06 - Said YOUS)