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

Abstract

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.