Design of selective ligands for the kainate subtype receptors

Based on the major role played by glutamate in our brain, the glutamatergic receptors constitute interesting targets to develop therapeutic drugs. Amongst all the pharmacological classes that have been investigated so far stand the AMPA receptor (AMPAR) positive allosteric modulators (AMPARpams).
For the last two decades, our laboratory has designed more than five hundred original 1,2,4-benzothiadiazine 1,1-dioxides and isosteres related to IDRA-21 acting as AMPARpams. Amongst the lead compounds, some ligands such as BPAM344 were co-crystallized with the ligand-binding domain (LBD) of the GluK1 subunit of kainate receptors (KARs). BPAM344 was shown to interact at the allosteric site of the GluK1-LBD dimer interface supporting the view that this drug behaves as a KARpam. This breakthrough was confirmed
after voltage-clamp experiments with homomeric GluK1b, GluK2a or GluK3 KARs expressed in HEK293 cells. BPAM344 was found to potentiate KARs, albeit at higher concentrations than required for potentiation of AMPA receptors .
Due to the structural analogy between AMPA and KA receptors and considering the recent knowledge of existing differences in residues at the level of their dimer interface after alignment of both receptors, a rational drug design leading to specific ligands for the KARs was explored.
Taking into account these data, the present work focused on the insertion of hydrocarbon chain bearing specific polar moieties on the nitrogen atom at the 4-position of BTDs with the aim to interact with specific amino-acid residues of the KAR allosteric site.