Electrophysiological Assessment of Newly Synthesized 2,3-Benzodiazepine Derivatives for Inhibiting the AMPA Receptor Channel

Abstract

Three major subtypes of ionotropic receptors regulate glutamatergic synaptic transmission, one of which is α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). They are tetrameric, cation-permeable ionotropic glutamate receptors found across the brain. Abnormalities in AMPA receptor trafficking and synaptic assembly are linked to cognitive decline and neurological diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. The present study will investigate the effects of four novel 2,3-benzodiazepine derivatives on AMPA receptor subunits by comparing their effects on synaptic responses, desensitization, and deactivation rate in human embryonic kidney cells (HEK293T) recombinant AMPAR subunits using whole-cell patch-clamp electrophysiology. All four 2,3-BDZ compounds showed inhibitory activity against all the homomeric and heteromeric subunits tested. While the desensitization and deactivation rates in 2,3-BDZ-1 and 2,3-BDZ-2 decreased and increased, respectively, in the other two compounds (i.e., 2,3-BDZ-3 and 2,3-BDZ-4), there was no change in the desensitization or deactivation rates. These results contribute to a better understanding of AMPARs by identifying potential 2,3-BDZ drugs that demonstrate inhibitory effects on the AMPAR subunits.

Multi-biological activity assessment and phytochemical characterization of an aqueous extract of the Cymbopogon citratus grown in Palestine

“…Transient transfections were facilitated using jetPRIME (Polyplus: New York, NY) [ 38 ]. Electrophysiological measurements were obtained via the whole-cell patch-clamp technique described in previous works [ 39 , 40 ]. Integrated Patch Clamp Amplifiers with Data Acquisition System (I.P.A., Sutter Instruments, Novato, CA) were employed for data acquisition.…”

Evaluating the Neuroprotective Potential of Novel Benzodioxole Derivatives in Parkinson’s Disease via AMPA Receptor Modulation

“…Cells were continuously washed using a double-barreled glass (theta tube) and a high-speed piezo solution switcher (Automate Scientific, Berkeley, CA) while being treated with the compound under investigation. Solution transitions ranged from 10–90% within 500 ms, with the open tip potential measured during the administration of varied ionic strength solutions resulting from patch ejection from the electrode, allowing for the calculation of solution exchange speed. − Viable cells were included in the sample size to record the mean inhibition caused by the targeted derivative. After each agonist washout, the cell’s health and data validation were ascertained by readministering control (glutamate), yielding results akin to those observed in glutamate-induced currents before derivative exposure (refer to Supporting Information for data).…”

“…In the neurobiological theater of PD, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have emerged as potential protagonists. These receptors, essential components of the glutamatergic system, orchestrate excitatory synaptic transmission in the brain. − They are integral to cognitive processes, such as learning and memory, and are pivotal agents in neuroplasticity, the brain’s remarkable ability to reorganize and adapt. , As part of their intricate functioning, AMPA receptors undergo dynamic processes of desensitizationa reduction in receptor responsiveness despite the continued presence of an agonistand deactivation, which pertains to the rapid termination of receptor activity once the agonist is removed. The balance between these processes ensures optimal neurotransmission. , However, overexcitation of AMPA receptors can lead to an excessive influx of calcium (Ca 2+ ) and sodium (Na + ) ions into the neuron, which can contribute to neuronal damage and is believed to be a potential mechanism involved in PD pathogenesis. , Their dysregulation is associated with many other neurodegenerative illnesses, including Alzheimer’s disease, Amyotrophic Lateral Sclerosis, and Huntington’s Disease, highlighting their crucial function in neural health. , AMPA receptors support synaptic strength optimally, allowing for effective information processing.…”