RÉSUMÉ
The past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A2A receptor (A2AAR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A2AAR antagonists with high ligand efficiency. This class of molecules has been discovered by a virtual screening and bears no structural semblance with reference antagonist ZM-241385. More precisely, we identified a series of 2-aminoquinazoline as promising A2AAR antagonists. Among them, one compound showed a high affinity towards A2AAR (21a, Ki = 20 nM). We crystallized this ligand in complex with A2AAR, confirming one of our predicted docking poses and opening up possibilities for further optimization to derive selective ligands for specific adenosine receptor subtypes.
Sujet(s)
Antagonistes des récepteurs A2 à l'adénosine , Antagonistes des récepteurs purinergiques P1 , Antagonistes des récepteurs A2 à l'adénosine/composition chimique , Antagonistes des récepteurs A2 à l'adénosine/pharmacologie , Ligands , Simulation de docking moléculaire , Antagonistes des récepteurs purinergiques P1/pharmacologie , Quinazolines/pharmacologie , Récepteur A2A à l'adénosine/composition chimique , Relation structure-activitéRÉSUMÉ
For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.
Sujet(s)
Acétamides/composition chimique , Phtalazines/composition chimique , Quinazolines/composition chimique , Récepteur de la mélatonine de type MT1/métabolisme , Récepteur de la mélatonine de type MT2/métabolisme , Acétamides/métabolisme , Animaux , Cellules CHO , Cricetinae , Cricetulus , Cellules HEK293 , Humains , Ligands , Phtalazines/métabolisme , Quinazolines/métabolisme , Relation structure-activitéRÉSUMÉ
Imidazo[1,2a]pyridines have gained much interest in the field of medicinal chemistry research. In the aim of accessing new privileged structure, we decided to design and synthesize 8-aminated-imidazo[1,2a]pyridines substituted on positions 2 and 6. This scaffold, rarely found in the literature, was obtained via palladium-catalyzed coupling reactions (Suzuki reaction or N-hydroxysuccinimidyl activated ester method) and tested on adenosine receptor A2A. We demonstrated how incorporation of an exocyclic amine enhanced affinity towards this receptor while maintaining low cytotoxicity.