Glutamate Regulation: Synthesis of Selective Positive Allosteric Modulators of the Kainic Acid Receptors belonging to 1,2,4-Benzothiadiazine 1,1-Dioxides

Given the important role of glutamate in brain function, there is a compelling interest in developing therapeutic drugs that target glutamatergic receptors. Among the various pharmacological classes being explored, AMPA receptor (AMPAr) positive allosteric modulators (AMPArPams) have received considerable attention.
Over the past two decades, our research laboratory has designed and synthesized several hundred original compounds belonging to the 1,2,4-benzothiadiazine-1,1-dioxide chemical class and related isosteres. Some of these compounds were found to act as potent positive allosteric modulators of AMPArs, with BPAM344 being a noticable example.
Recent advances in structural studies allowed the characterization of the subunit components of kainic acid receptors (KArs), in particular their allosteric binding pocket located at the level of the ligand binding domain of the receptor. Recent studies revealed that some of our compounds such as BPAM344, a well-known AMPArPam, can also act as a positive allosteric modulator of KArs.
As a result of these investigations, we designed a first series of original benzothiadiazine dioxides based on the initial observations. This allowed us to better understand the interactions between these molecules and the binding domains of KArs. Our current studies are focused on developing molecules that can be used as "probes" expected to fill the allosteric pocket of the receptor to improve our knowledge of the binding site interactions. These modulators will also be designed to obtain a selectivity towards the GluK1-3 or GluK4-5 subunits of KArs.