Neuropharmacological research has focused on discovering effective and safe medications for treating neurological illnesses caused by glutamate toxicity. They are specifically looking for antagonists to alter the activity and kinetics of AMPA receptors, which are the fastest ligand-gated ion channels involved in glutamate-induced excitatory neurotransmission. As a result, our present research has focused on developing antagonists that alter the biophysical gating properties of AMPA receptors, namely 2,3-benzodiazepine (2,3-BDZ) derivatives, which act as negative allosteric modulators by binding to transducer domains and preventing channel gating. Understanding how AMPA receptors function and interact with their antagonists may aid in developing novel CNS drugs. The biophysical parameters (desensitization, deactivation, and peak currents) were assessed with and without the delivery of the derivatives onto Human Embryonic Kidney cells (HEK293) using whole-cell patch clamp electrophysiology.The inhibition caused by the 2,3-BDZ derivatives was because of an allosteric blocking mechanism that lowered whole-cell currents by 5-8-fold. Regarding the structure-activity relationship, our findings revealed that adding an electron-withdrawing group (i.e., Cl or Br) inhibited AMPA receptors and influenced AMPA receptor kinetics. Furthermore, the phenyl ring of 2,3-BDZ is needed for AMPA receptor binding. When an electron-withdrawing group is introduced to the meta position of the BDZ phenyl ring, the amino group is no longer necessary for inhibition.2,3-BDZ derivatives have the potential to change our knowledge of and approach to treating CNS illnesses. Using our data, we can better understand the therapeutic effects of these drugs in the future. More investigation into the AMPAR-antagonist interaction may lead to more accurate development of antagonists that target AMPARs.

Title

Biopyhsical Journal

Publisher

Cell Press

Publisher Country

United States of America

Indexing

Thomson Reuters

Impact Factor

3.699

Publication Type

Prtinted only

Volume

122

Year

2023

Pages

418a