The AMPA receptor biophysical gating properties and binding site: Focus on novel curcumin-based diazepines as non-competitive antagonists

Mohammad Qneibi*, Othman Hamed, Nidal Jaradat, Mohammed Hawash, Rana Al-Kerm, Rola Al-Kerm, Shorooq Sobuh, Sama Tarazi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Introduction: Investigating the binding site of six novel curcumin-based diazepine compounds as a non-competitive antagonist on ionotropic, AMPA-type glutamate receptors, including homomeric and heteromeric subunits. These receptors play a pivotal role in neurodegenerative diseases such as Alzheimer's and epilepsy due to excitotoxicity. Furthermore, it appears that AMPAR signaling plays a significant role in disease development outside the nervous system, as a potential relationship between AMPAR activation and cancer development may exist. Objectives: Study the biophysical gating effects of the curcumin-based diazepine on AMPAR variants and identify CBD binding sites on AMPARs with the hopes of discovering more potent drug candidates with less undesirable side effects. Methods: Our current study uses patch-clamp electrophysiology technology to estimate whole-cell amplitudes changes when exposing HEK293T cells expressing AMPAR subunits to different curcumin-based diazepines. Results: The non-competitive antagonist curcumin-based compounds successfully reduced AMPAR activation currents and increased the rate of desensitization and deactivation. CBD-4 and CBD-5 show the most significant impact on AMPARs, reducing the current by 7-fold. The results contrast with those obtained by the halogenated benzodiazepine-fused curcumins reported previously and lake pyrimidine and pyrazine moieties. This indicates that the N's presence in the effused rings plays a significant role in binding to receptors. CBD-4 showed the highest effect on GluA2 subunits in receptors, while CBD-5 most dramatically impacting GluA1 homomeric receptors, demonstrating that the compounds are more selective towards AMPA-type glutamate receptors. The compounds also showed significant cytotoxic activities against breast cancer cell line (MCF-7), with CBD-4 having the most significant impact. Conclusion: Curcumin-based compounds (i.e., CBD-4 and CBD-5) yield significant neurodegenerative drug potential, and it creates a novel structure with significant activities in reducing AMPAR excitation compared to traditional benzodiazepine analogs, yet their binding mechanisms are still not fully understood. Moreover, AMPARs appear to have a potential influence on cancer development, and the curcumin-based compounds might provide insight into the nature of this relationship.

Original languageAmerican English
Article number105406
JournalBioorganic Chemistry
Volume116
DOIs
StatePublished - Nov 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • AMPAR
  • Biophysical gating properties
  • Curcumin-based diazepine
  • Excitotoxicity
  • Inhibition
  • Neurodegenerative

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