Evaluating the Neuroprotective Potential of Novel Benzodioxole Derivatives in Parkinson’s Disease via AMPA Receptor Modulation

Mohammed Hawash*, Mohammad Qneibi*, Hiba Natsheh, Noor Haj Mohammed, Lubaba Abu Hamda, Anil Kumar, Barbara Olech, Paulina Maria Dominiak, Sosana Bdir, Mohammad Bdair

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson’s disease (PD) is a significant health issue because it gradually damages the nervous system. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play a significant role in the development of PD. The current investigation employed hybrid benzodioxole-propanamide (BDZ-P) compounds to get information on AMPA receptors, analyze their biochemical and biophysical properties, and assess their neuroprotective effects. Examining the biophysical characteristics of all the subunits of the AMPA receptor offers insights into the impact of BDZ-P on the desensitization and deactivation rate. It demonstrates a partial improvement in the locomotor capacities in a mouse model of Parkinson’s disease. In addition, the in vivo experiment assessed the locomotor activity by utilizing the open-field test. Our findings demonstrated that BDZ-P7 stands out with its remarkable potency, inhibiting the GluA2 subunit nearly 8-fold with an IC50 of 3.03 μM, GluA1/2 by 7.5-fold with an IC50 of 3.14 μM, GluA2/3 by nearly 7-fold with an IC50 of 3.19 μM, and GluA1 by 6.5-fold with an IC50 of 3.2 μM, significantly impacting the desensitization and deactivation rate of the AMPA receptor. BDZ-P7 showed an in vivo impact of partially reinstating locomotor abilities in a mouse model of PD. The results above suggest that the BDZ-P7 compounds show great promise as top contenders for the development of novel neuroprotective therapies.

Original languageAmerican English
JournalACS Chemical Neuroscience
DOIs
StateAccepted/In press - 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 American Chemical Society.

Keywords

  • AMPA receptor
  • benzodioxole-propanamide
  • MicroED
  • Parkinson’s disease

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