Targeting the kinetics mechanism of AMPA receptor inhibition by 2-oxo-3H-benzoxazole derivatives

Qneibi, Mohammad; Hawash, Mohammed; Bdir, Sosana; Baytas, Sultan Nacak

doi:10.1016/j.bioorg.2022.106163

Cited by 7 publications

(2 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These interactions can lead to anticonvulsant properties, with carbonyl groups, heteroatoms, and aromatic or heterocyclic rings playing pivotal roles in these pharmacophore groups. In our previous research on 2-oxo-3Hbenzoxazole derivatives, these compounds exhibited essential pharmacophores that interact with amino acids in the binding site of AMPA receptor subunits, resulting in receptor inhibition and potential anticonvulsant effects [38]. Previous research has identified critical residues surrounding the binding pocket, including the pre-M1, M3, and M4 helices, as well as the S2-M4 linker.…”

Section: Thiazole Derivatives' Effects On Glua2 Currents and Kinetics...mentioning

confidence: 99%

Thiazole Derivatives as Modulators of GluA2 AMPA Receptors: Potent Allosteric Effects and Neuroprotective Potential

Hawash

2023

Biomolecules

Self Cite

View full text Add to dashboard Cite

Thiazole carboxamide derivatives were synthesized in this investigation, with a subsequent examination of their impact on GluA2 AMPA receptors. The synthesized compounds, namely MMH-1-5, were subjected to characterization using high-resolution mass spectrometry (HRMS), proton nuclear magnetic resonance (1H-NMR), and carbon-13 nuclear magnetic resonance (13C-NMR). The present work thoroughly investigates the impact of five thiazole derivatives on GluA2 AMPA receptors. This investigation examined their effects on both whole-cell currents and receptor kinetics. In addition, the cytotoxicity of the samples was assessed using the MTS test. The compound MMH-5 had the highest effect level, resulting in a notable drop in current amplitude by a factor of six. Similarly, MMH-4 and MMH-3 also caused major reductions in the current amplitude. The compounds mentioned above also influenced the rates of deactivation and desensitization. MMH-5 and MMH-4 exhibited an increase in deactivation, while MMH-5 showed reduced desensitization. Our research findings highlight the efficacy of MMH-5 as a negative allosteric modulator of GluA2 AMPA receptors, exerting substantial effects on both the magnitude and time course of receptor activity. Significantly, the compound MMH-2 demonstrated noteworthy cytotoxic effects, as evidenced by cell viability rates dropping below 6.79% for all cancer cell lines and 17.52% for the normal cell line (LX-2). Of particular interest is the pronounced cytotoxicity observed in MMH-5, suggesting its potential as a safe neuroprotective agent targeting the AMPA receptor, as indicated by cell viability percentages exceeding 85.44% across all cancer and normal cell lines. Docking simulations were performed to determine possible modes of interaction between MMH5 and the GluA2-AMPA receptor (PDB:7RZ5). The abovementioned facts and the well-documented effects of further thiazole derivatives provide a strong foundation for future research endeavors to enhance tailored treatments for neurological disorders that rely heavily on GluA2 signaling. The present study elucidates the intricate association between thiazole derivatives and GluA2 receptors, providing valuable perspectives on the prospects of enhanced and specific therapeutic interventions for diverse neurological conditions.

show abstract

Section: Thiazole Derivatives' Effects On Glua2 Currents and Kinetics...mentioning

confidence: 99%

Thiazole Derivatives as Modulators of GluA2 AMPA Receptors: Potent Allosteric Effects and Neuroprotective Potential

Hawash

2023

Biomolecules

Self Cite

View full text Add to dashboard Cite

show abstract

“…These include combating schistosomiasis, countering epilepsy, alleviating pain, battling tuberculosis, and demonstrating antimicrobial prowess. The presence of this core structure in natural sources and its versatility in creating biologically active compounds make it a promising target for further research and pharmaceutical development [16][17][18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Characterization and Investigation of Novel Benzodioxol Derivatives as Antidiabetic Agents: An In Vitro and In Vivo Study in an Animal Model

Hawash,

Al-Smadi,

Kumar

et al. 2023

Biomolecules

Self Cite

View full text Add to dashboard Cite

In this study, we synthesized benzodioxol carboxamide derivatives and investigated their antidiabetic potential. The synthesized compounds (Ia-Ic and IIa-IId) underwent characterization via HRMS, 1H-, 13CAPT-NMR, and MicroED. Their efficacy against α-amylase was assessed in vitro, while MTS assays were employed to gauge cytotoxicity across cancer and normal cell lines. Additionally, the antidiabetic impact of compound IIc was evaluated in vivo using a streptozotocin-induced diabetic mice model. Notably, IIa and IIc displayed potent α-amylase inhibition (IC50 values of 0.85 and 0.68 µM, respectively) while exhibiting a negligible effect on the Hek293t normal cell line (IC50 > 150 µM), suggesting their safety. Compound IId demonstrated significant activity against four cancer cell lines (26–65 µM). In vivo experiments revealed that five doses of IIc substantially reduced mice blood glucose levels from 252.2 mg/dL to 173.8 mg/dL in contrast to the control group. The compelling in vitro anticancer efficacy of IIc and its safety for normal cells underscores the need for further in vivo assessment of this promising compound. This research highlights the potential of benzodioxol derivatives as candidates for the future development of synthetic antidiabetic drugs.

show abstract

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

Qneibi,

Hawash,

Gümüş

et al. 2023

Mol Neurobiol

View full text Add to dashboard Cite

Targeting the kinetics mechanism of AMPA receptor inhibition by 2-oxo-3H-benzoxazole derivatives

Cited by 7 publications

References 41 publications

Thiazole Derivatives as Modulators of GluA2 AMPA Receptors: Potent Allosteric Effects and Neuroprotective Potential

Thiazole Derivatives as Modulators of GluA2 AMPA Receptors: Potent Allosteric Effects and Neuroprotective Potential

Characterization and Investigation of Novel Benzodioxol Derivatives as Antidiabetic Agents: An In Vitro and In Vivo Study in an Animal Model

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

Contact Info

Product

Resources

About