Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

Abstract

Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward ‘non-NMDA’ (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds.

Gluk4-containing kainate receptors regulate synaptic communication in the motor cortex and reduce axon degeneration in adult mice

“…Kainate receptors protecting against neurodegeneration maybe unexpected, given their established role as mediators of excitotoxic injury (Chalupnik and Szymanska, 2023). Indeed, mice that lack functional Gluk4-kainate receptors experience less hippocampal neurodegeneration following an ischemic stroke (Lowry et al ., 2013).…”

Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection

“…Nevertheless, recent advances in the field have shed light on the function and regulation of KARs, including the discovery of competitive and noncompetitive KAR antagonists that hold therapeutic potential. 46 Additionally, cryo-electron microscopy structures have provided insights into the allosteric modulation of KARs by small molecules, such as positive allosteric modulators like BPAM344 and negative allosteric modulators like antiepileptic drug perampanel. 47 These findings offer promising directions for exploring KARs as potential drug targets to address CNS disorders and pave the way for further research in understanding the complexities of KAR biology and its implications in neuronal communication and modulation.…”

“…However, compared to other GluRs, such as AMPARs, progress in understanding KARs has been hampered by a lack of specific and selective pharmacological tools. Nevertheless, recent advances in the field have shed light on the function and regulation of KARs, including the discovery of competitive and noncompetitive KAR antagonists that hold therapeutic potential 46 . Additionally, cryo‐electron microscopy structures have provided insights into the allosteric modulation of KARs by small molecules, such as positive allosteric modulators like BPAM344 and negative allosteric modulators like antiepileptic drug perampanel 47 .…”

Update on neurobiological mechanisms of fear: illuminating the direction of mechanism exploration and treatment development of trauma and fear-related disorders

“…mGLuRs contain a train of receptors. As G protein-coupled receptors, they can work through a second messenger system (Chałupnik and Szymańska, 2023 ).…”