The effect of novel negative allosteric 2,3-benzodiazepine on glutamate AMPA receptor and their cytotoxicity

Jaradat, Nidal; Hawash, Mohammed; Qneibi, Mohammad; Shtayeh, Tahrir; Sobuh, Shorooq; Arar, Mohammed; Bdir, Sosana

doi:10.1016/j.molstruc.2022.132936

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…Additionally, aromatic or heterocyclic rings contribute to hydrophobic interactions . Moreover, the presence of halogen atoms, namely, chlorine (Cl) or bromine (Br), has been noted to augment the inhibitory effects on AMPA receptors. , Chlorine-containing compounds exhibit greater potency than those with bromine or iodine, attributed to chlorine’s more pronounced electron-withdrawing properties than other halogens. Each of these structural components holds significant value as pharmacophores, facilitating substantial binding interactions with different subtypes of AMPA receptors.…”

Section: Resultsmentioning

confidence: 99%

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

Hawash,

Qneibi,

Natsheh

et al. 2024

ACS Chem. Neurosci.

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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.

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Section: Resultsmentioning

confidence: 99%

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

Hawash,

Qneibi,

Natsheh

et al. 2024

ACS Chem. Neurosci.

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“…The specific characteristics of these interactions may exhibit variability contingent upon the subunit composition of the receptor complex. By using advanced computational methods and doing mutagenesis studies, we might be able to learn more about the specific binding mechanisms and essential amino acid residues that are key to these interactions [ 25 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, evidence indicates that several chemical groups can engage with the AMPA receptor at allosteric modulatory sites, resulting in alterations in the gating mechanism of the receptor, including processes such as activation, deactivation, and desensitization. Multiple allosteric modulators, such as 2,3-BDZ, have been extensively researched for their effects on the processes of desensitization and deactivation [ 9 , 23 , 24 , 25 ]. The area of 2,3-BDZ compounds has seen notable advancements, resulting in new compounds with distinct and exceptional characteristics.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, compounds 4b and 4e exhibited promising cytotoxicity against diverse cancer cell lines. As mentioned, the information enhances comprehension about AMPARs, presents alternative medication candidates of 2,3-BDZ distinct from standard derivatives, and potentially functions as neuroprotective agents [ 25 , 34 ]. However, it is uncertain how much chemical structural changes affect the selectivity of newly synthesized drugs for AMPA receptors.…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological Assessment of Newly Synthesized 2,3-Benzodiazepine Derivatives for Inhibiting the AMPA Receptor Channel

et al. 2023

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Three major subtypes of ionotropic receptors regulate glutamatergic synaptic transmission, one of which is α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). They are tetrameric, cation-permeable ionotropic glutamate receptors found across the brain. Abnormalities in AMPA receptor trafficking and synaptic assembly are linked to cognitive decline and neurological diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. The present study will investigate the effects of four novel 2,3-benzodiazepine derivatives on AMPA receptor subunits by comparing their effects on synaptic responses, desensitization, and deactivation rate in human embryonic kidney cells (HEK293T) recombinant AMPAR subunits using whole-cell patch-clamp electrophysiology. All four 2,3-BDZ compounds showed inhibitory activity against all the homomeric and heteromeric subunits tested. While the desensitization and deactivation rates in 2,3-BDZ-1 and 2,3-BDZ-2 decreased and increased, respectively, in the other two compounds (i.e., 2,3-BDZ-3 and 2,3-BDZ-4), there was no change in the desensitization or deactivation rates. These results contribute to a better understanding of AMPARs by identifying potential 2,3-BDZ drugs that demonstrate inhibitory effects on the AMPAR subunits.

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“…Controlling AMPAR activity is being investigated as a potential treatment for neurological and psychiatric conditions. Even though there has been an increase in the development of AMPAR positive and negative allosteric modulators (PAMs and NAMs) [ 20 ], they have been found to lack selectivity for distinct brain areas [ 21 , 22 , 23 ]. For example, the NAM perampanel is effective against various seizure types, but its lack of regional specificity leads to side effects such as ataxia and dizziness [ 22 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors’ Gating Modules

Qneibi

Nassar²,

Bdir³

et al. 2022

Cells

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The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring compound, which functions as a co-factor in metabolism and energy production. α-LA is an antioxidant with various benefits in treating diabetes, including managing symptomatic diabetic neuropathy. This study will test a novel and innovative strategy to synthesize a new isomer of lipoic acid (R-LA) derivatives (bifunctional NO-donor/antioxidant) in one chemical on homomeric and heteromeric AMPA receptor subunits. We used patch-clamp electrophysiology to examine LA derivatives expressed in human embryonic kidney 293 cells (HEK293) for inhibition and changes in desensitization or deactivation rates. LA derivatives were shown to be potent antagonists of AMPA receptors, with an 8–11-fold reduction in AMPA receptor currents seen following the delivery of the compounds. Furthermore, the LA derivatives influenced the rates of desensitization and deactivation of AMPA receptors. Based on our results, especially given that α-LA is closely connected to the nervous system, we may better understand using AMPA receptors and innovative drugs to treat neurological diseases associated with excessive activation of AMPA receptors.

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The effect of novel negative allosteric 2,3-benzodiazepine on glutamate AMPA receptor and their cytotoxicity

Cited by 8 publications

References 29 publications

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

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

Electrophysiological Assessment of Newly Synthesized 2,3-Benzodiazepine Derivatives for Inhibiting the AMPA Receptor Channel

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors’ Gating Modules

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