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Deciphering the Biophysical Properties of Ion Channel Gating Pores by Coumarin–Benzodiazepine Hybrid Derivatives: Selective AMPA Receptor Antagonists

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Abstract

In the 1980s, the identification of specific pharmacological antagonists played a crucial role in enhancing our comprehension of the physiological mechanisms associated with α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). The primary objective of this investigation was to identify specific AMPA receptor antagonists, namely 2,3-benzodiazepines, that function as negative allosteric modulators (NAMs) at distinct locations apart from the glutamate recognition site. These compounds have exhibited a diverse array of anticonvulsant properties. In order to conduct a more comprehensive investigation, the study utilized whole-cell patch-clamp electrophysiology to analyze the inhibitory effect and selectivity of benzodiazepine derivatives that incorporate coumarin rings in relation to AMPA receptors. The study’s main objective was to acquire knowledge about the relationship between the structure and activity of the compound and comprehend the potential effects of altering the side chains on negative allosteric modulation. The investigation provided crucial insights into the interaction between eight CD compounds and AMPA receptor subunits. Although all compounds demonstrated effective blockade, CD8 demonstrated the greatest potency and selectivity towards AMPA receptor subunits. The deactivation and desensitization rates were significantly influenced by CD8, CD6, and CD5, distinguishing them from the remaining five chemicals. The differences in binding and inhibition of AMPA receptor subunits can be attributed to structural discrepancies among the compounds. The carboxyl group of CD8, situated at the para position of the phenyl ring, substantially influenced the augmentation of AMPA receptor affinity. The findings of this study highlight the potential of pharmaceutical compounds that specifically target AMPA receptors to facilitate negative allosteric modulation.

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Data Availability

Data collected or analyzed in this investigation are included in this manuscript and its supplemental material file.

Abbreviations

CD:

coumarin-benzodiazepine hybrid compounds

iGluRs:

ionotropic glutamate receptors

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

NMDA:

N-methyl-D-aspartate

HEK293:

human embryonic kidney 293 cells

AMPARs:

AMPA receptors

CNS:

central nervous system

NTD:

N-terminal extracellular amino domain

LBD:

ligand binding domain

TMD:

transmembrane domain

LTP:

long-term potentiation

LTD:

long-term depression

NAM:

negative allosteric modulator

PAM:

positive allosteric modulator

GFP:

green fluorescent protein

DMF:

N, N-dimethylformamide

ANOVA:

a one-way analysis of variance

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Acknowledgements

The authors are grateful to An-Najah National University (www.najah.edu) for its support in this research.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine

    Mohammad Qneibi, Sosana Bdir & Mohammad Bdair

  2. Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine

    Mohammed Hawash

  3. Akdagmadeni Health College, Yozgat Bozok University, Yozgat, Turkey

    Mehmet Gümüş

  4. Technical Sciences Vocational College, Department of Material and Material Processing Technologies, Gazi University, 06560, Ankara, Turkey

    İrfan Çapan

  5. Basic and Engineering Sciences Central Laboratory Application and Research Center (GUTMAM), Gazi University, 06500, Ankara, Turkey

    İrfan Çapan

  6. Sorgun Vocational School, Yozgat Bozok University, Yozgat, Turkey

    Yusuf Sert

  7. Department of Chemistry, Faculty of Art & Sciences, Yozgat Bozok University, Yozgat, Turkey

    İrfan Koca

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  1. Mohammad Qneibi
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Contributions

Mohammad Qneibi: conceptualization, methodology, validation, investigation, writing—original draft, manuscript drafting, data curation, and project. Mohammed Hawash: validation, data curation, and manuscript drafting. Mehmet Gümüş: synthesis. İrfan Çapan: validation. Yusuf Sert: validation. Sosana Bdir: validation and manuscript drafting. İrfan Koca: Synthesis and manuscript drafting. Mohammad Bdair: manuscript drafting.

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Correspondence to Mohammad Qneibi.

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Qneibi, M., Hawash, M., Gümüş, M. et al. Deciphering the Biophysical Properties of Ion Channel Gating Pores by Coumarin–Benzodiazepine Hybrid Derivatives: Selective AMPA Receptor Antagonists. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03871-1

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