Abstract :
[en] Glutamate is the principal excitatory neurotransmitter in the brain, and glutamatergic receptors are therefore attractive targets for therapeutic intervention. Among the different pharmacological approaches, positive allosteric modulators (PAMs) of AMPA and kainate receptors (AMPA/KARPAMs) are particularly promising, as they enhance receptor activity in a more controlled and subtle manner than direct agonists, thereby helping to stabilize neuronal excitability and support overall brain function.
Studies in Alzheimer’s disease models consistently report a loss of GluK2 containing kainate receptors (KARs) [1–2], accompanied by impaired synaptic currents and reduced neuronal communication that may contribute to cognitive deficits [3]. The amyloid precursor protein (APP) is crucial for maintaining KAR stability, and its disruption in Alzheimer’s disease further diminishes GluK2 subunit levels and KAR function, leading to additional weakening of synaptic transmission [4]. Positive allosteric modulation of GluK2-containing KARs could therefore represents a promising therapeutic strategy.
Advances in structural analysis have provided detailed insights into the subunit composition of kainate receptors (KArs), particularly concerning the allosteric binding site within the ligand-binding domain. Recent studies have shown that certain compounds developed in our laboratory, including BPAM344, act as positive allosteric modulators of KARs [5].
Building on these findings, we designed a first series of novel benzothiadiazine dioxides inspired by BPAM344 and related structures. This work has enhanced our understanding of how these molecules interact with the allosteric binding domains of KArs. Our ongoing efforts, including molecular modeling studies, aim to develop compounds that efficiently target the allosteric pocket, with a particular focus on achieving subunit selectivity between GluK1-3 and GluK4-5 receptors.
[1] : Carta, M et al., Eur. J. Neurosci. 2014, 39, 1835–1844.
[2] : Mulle,C. & Crépel,V.Neuropharmacology, 2021,197,108699.
[3] : Gautam, D et al. Biomolecules 2023, 13 (11), 1609.
[4] : Barthet,G et al. J. Neurosci. 2022, 42, 9253–9262.
[5] : Larsen AP et al., Mol. Pharmacol. 2017 Jun;91, 576.
