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. (C) 2015 Elsevier Ltd. All rights reserved.