Discovery of novel small-molecule antagonists for GluK2.
KA receptors have shown to be potential therapeutic targets in CNS diseases such as schizophrenia, depression, neuropathic pain and epilepsy. Through the use of our docking tool Fitted, we investigated the relationship between ligand activity towards GluK2 and the conformational state induced at the receptor level. By focusing our rational design on the interaction between the ligand and a tyrosine residue in the binding site, we synthesized a series of molecules based on a glutamate scaffold, and carried out electrophysiological recordings. The observed ability of some of these molecules to inhibit receptor activation shows the potential of our design for the development of effective antagonists with a molecular size comparable to that of the endogenous neurotransmitter L-glutamate.
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
Paolo
P
Schiavini
Integrated Program in Neuroscience, McGill University, Canada; Department of Pharmacology, McGill University, 3649 Promenade Sir William Osler, Montréal, Québec H3G 0B1, Canada.
G Brent
GB
Dawe
Department of Pharmacology, McGill University, 3649 Promenade Sir William Osler, Montréal, Québec H3G 0B1, Canada.
Derek
D
Bowie
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada. Electronic address: nicolas.moitessier@mcgill.ca.
Nicolas
N
Moitessier
D020134:Catalytic Domain; D002491:Central Nervous System Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D012984:Software; D000097806:GluK2 Kainate Receptor
D002491:Central Nervous System Agents; D008024:Ligands; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor
Antagonist; Flexible docking; GluK2; Kainate receptor; Rational design