Advances in Targeting Kainic Acid Receptors: Developing Selective Positive Allosteric Modulators from the 1,2,4-Benzothiadiazine 1,1-Dioxide scaffold

Due to glutamate's crucial role in brain function, there is a considerable interest in the development of therapeutics targeting specific glutamatergic receptors. Among these, positive allosteric modulators (PAMs) of AMPA receptors (AMPArPams) and more recently, kainate receptors (KArPams), have drawn significant attention. In particular, the latter appears to reduce the excitability of glutamatergic pathways, contributing to neuronal stability.

Over the past two decades in our laboratory, extensive effort has focused on developing and synthesizing numerous original compounds from the 1,2,4-benzothiadiazine 1,1-dioxide class and related analogues. Some of these compounds demonstrated potent activity as positive allosteric modulators of AMPA receptors, from which BPAM344 being a notable example.

Progress in structural analysis provided insights into kainic acid receptors (KArs), particularly regarding the allosteric binding site within the receptor's ligand-binding domain (LBD). Recent research revealed that certain compounds developed in our lab, including BPAM344, also exhibited positive allosteric modulation of KArs. Further investigations highlighted that specific substitution of the benzothiadiazine structure enhanced positive allosteric modulation of KArs.

These findings guided the design of a new series of benzothiadiazine dioxides, building upon initial observations with BPAM344 and related structures. This facilitated a deeper understanding of how these molecules interact with KArs' binding domains. Our ongoing investigations, including molecular modeling, aim to develop compounds effectively occupying the receptor's allosteric pocket. We're also striving to obtain modulators with selectivity for either the GluK1-3 or GluK4-5 subunits of KArs.