Developing selective positive allosteric modulators for kainic acid receptors using the 1,2,4-benzothiadiazine 1,1-dioxide scaffold

Due to wide implication of glutamate in brain function, there is a significant interest in the development of therapeutic drugs targeting glutamatergic receptors. Among the various drug classes under investigation for this purpose, positive allosteric modulators (PAMs) of AMPA and kainate receptors (AMPA/KA-rPAMs) have attracted a particular attention. These modulators appear to modulate the excitability of glutamatergic pathways contributing to the maintaining of neuronal stability.
Since the 90s, our laboratory has been actively developing a wide range of original compounds belonging to the 1,2,4-benzothiadiazine 1,1-dioxide chemical class and related isosteric analogs. Some of these compounds have demonstrated potent activity as positive allosteric modulators of AMPA receptors, with BPAM121 and BPAM344 being standout examples.
Advances in structural analysis have provided insights into the subunit composition of kainate receptors (KArs), particularly regarding the allosteric binding site located within the ligand-binding domain of the receptor. Recent research have revealed that certain compounds developed in our laboratory, including BPAM344, exhibit positive allosteric modulation of KArs.
These discoveries enabled the design of a first series of novel benzothiadiazine dioxides based on the observations with BPAM344 and related structures. This deepened our understanding of how these molecules interact with the binding domains of KArs. Our ongoing investigations, including molecular modeling, are focused on developing compounds that can effectively bind to the allosteric pocket of the receptor. Additionally, attention is directed towards obtaining modulators with selectivity for either the GluK1-3 or GluK4-5 subunits of KArs.