Parkinson's disease (PD) is characterized by progressive neurodegeneration that affects both motor and cognitive functions, driven by complex interactions between genetic and environmental factors. The glutamatergic system, particularly the role of ionotropic glutamate receptors such as AMPA receptors, has gained attention as a critical player in the pathophysiology of PD. Modulation of these receptors can mitigate excitotoxicity and neuronal damage. Our study explored benzodioxole (BDX) derivatives, a novel class of compounds designed to fine-tune AMPA receptor kinetics. These compounds incorporate targeted structural modifications to enhance allosteric modulation, offering a potential therapeutic strategy to restore synaptic function and motor performance in PD models. To evaluate the neuropharmacological effects of BDX-P derivatives, we utilized whole-cell patch-clamp electrophysiology on HEK293T cells expressing specific AMPA receptor subunits, allowing for precise desensitization and deactivation kinetics measurement in response to the compounds. For in-vivo evaluation, we employed a reserpine-induced PD mouse model, administering BDX-P derivatives daily over two weeks. Locomotor function was assessed using the open-field test, quantifying spontaneous activity as a marker of motor recovery and synaptic restoration. BDX-P derivatives significantly modulated AMPA receptor activity, with one compound, in particular, showing the most pronounced effects, especially on the GluA2 subunit. Adding functional groups, including propanamide and halogen atoms, improved desensitization and deactivation rates. In vivo, the treatment markedly improved locomotor function, as evidenced by increased movement in the open-field test, indicating restored motor function. Incorporating functional groups into BDX-P derivatives significantly enhanced their ability to regulate AMPA receptor activity, particularly impacting the GluA2 subunit. Structural modifications in BDX-P7 enhanced AMPA receptor activity in vitro and improved motor function and synaptic activity in vivo, suggesting its potential therapeutic benefits. These findings highlight BDX-P compounds as promising candidates for modulating AMPA receptors.

Conference Title

Biophysical society annual meeting los angeles california

Conference Country

United States of America

Conference Date

Feb. 13, 2025 - Feb. 19, 2025

Conference Sponsor

Biophysical socity

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