Kainic Acid Receptors: Innovating Selective Positive Allosteric Modulators based on 1,2,4-Benzothiadiazine 1,1-Dioxides

Because of the important role of glutamate in brain function, there is a strong interest in developing therapeutic drugs that specifically target glutamatergic receptors. Among the various classes of drugs being investigated for this purpose, particular attention has been paid to positive allosteric modulators (PAMs) of AMPA receptors (AMPArPAMs) and, more recently, of kainate receptors (KArPAMs). These last modulators seem to promote a down-regulation of the excitability of glutamatergic pathways that contributes to the stability of neurons.
In our laboratory, the last two decades have been focused on the development and synthesis of numerous original compounds belonging to the 1,2,4-benzothiadiazine 1,1-dioxide chemical class and to related isosteric analogues. Some of these compounds were found to express potent activity as positive allosteric modulators of the AMPA receptors. BPAM344 stands out as an example of such a compound.
Advances in structural analysis provided insight into the subunit composition of kainic acid receptors (KArs), particularly with respect to the allosteric binding site located within the ligand-binding domain of the receptor. Recent research showed that some of the compounds developed in our laboratory, including BPAM344, also exhibited positive allosteric modulation of KArs. Further investigations have also shown that the benzothiadiazine structure with an allyl chain on the nitrogen atom at the 4-position also improved the positive allosteric modulation of KArs.
A first series of novel benzothiadiazine dioxides has been designed on the preliminary observations with BPAM344 and related structures. This led to gain a deeper understanding of how these molecules interact with the binding domains of KArs. Our ongoing investigations included molecular modeling and are focused on developing compounds that can effectively occupy the allosteric pocket of the receptor. Attention is also paid to obtain modulators with selectivity for either the GluK1-3 or GluK4-5 subunits of KArs.