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GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
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Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators.

Mohammad Qneibi1, Mohammad Hawash2, Nidal Jaradat2

  • 1Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine. mqneibi@najah.edu.

Molecular Neurobiology
|June 10, 2022
PubMed
Summary

Benzodioxole (BDZ) derivatives act as negative allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. These compounds show potential for neuroprotection by reestablishing glutamatergic synaptic transmission in the central nervous system.

Keywords:
AMPA receptorAllostericBenzodioxole derivativesDeactivationDesensitizationNeurodegenerative

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Glutamatergic synapses, utilizing α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, are crucial for excitatory neurotransmission in the central nervous system (CNS).
  • Dysregulation of AMPA receptor-mediated transmission is implicated in neurological disorders such as Alzheimer's, Parkinson's, depression, and epilepsy.
  • Developing compounds to modulate AMPA receptor (AMPAR) signaling is a key therapeutic strategy for these conditions.

Purpose of the Study:

  • To investigate the allosteric modulating effects of benzodioxole (BDZ) derivatives on AMPA receptors.
  • To compare the actions of BDZ derivatives on AMPA-evoked currents, desensitization, and deactivation rates.
  • To explore the potential of BDZ compounds as neuroprotective agents by reestablishing glutamatergic synaptic transmission.

Main Methods:

  • Utilized human embryonic kidney (HEK293T) cells expressing recombinant AMPAR subunits.
  • Employed patch-clamp electrophysiology to record AMPA-evoked currents.
  • Assessed the impact of BDZ derivatives on AMPAR desensitization and deactivation kinetics.

Main Results:

  • BDZ derivatives were identified as negative allosteric modulators of AMPA receptors.
  • Specific BDZs (compounds 8, 9, and 15) significantly increased AMPAR desensitization rates.
  • These BDZ compounds also demonstrated a delay in the deactivation process of AMPARs.

Conclusions:

  • BDZ derivatives effectively modulate AMPA receptor function, acting as negative allosteric modulators.
  • The identified BDZ compounds hold potential for therapeutic applications in neurological diseases characterized by glutamatergic dysfunction.
  • These molecules represent promising candidates for developing neuroprotective strategies targeting AMPA receptor pathways.