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In addition to their wide therapeutic application, benzoates and benzoic acid derivatives are the most commonly utilized food preservatives. The purpose of this study was to estimate the antioxidant, anti-diabetic, and anti-obesity activities of four 2-(phenylthio)-ethyl benzoate derivatives utilizing standard biomedical assays. The results revealed that the 2a compound has potent antidiabetic activity through the inhibition of α-amylase and α-glycosidase with IC 50 doses of 3.57 ± 1.08 and 10.09 ± 0.70 µg/ml, respectively, compared with the positive control acarbose (IC 50  = 6.47 and 44.79 µg/ml), respectively. In addition, by utilizing the β-carotene linoleic acid and DPPH methods, the 2a compound showed the highest antioxidant activity compared with positive controls. Moreover, the 2a compound showed potential anti-lipase activity with an IC 50 dose of 107.95 ± 1.88 µg/ml compared to orlistat (IC 50  = 25.01 ± 0.78 µg/ml). A molecular docking study was used to understand the interactions between four derivatives of (2-(phenylthio)-ethyl benzoate with α-amylase binding pocket. The present study concludes that the 2a compound could be exploited for further antidiabetic, antioxidant, and anti-obesity preclinical and clinical tests and design suitable pharmaceutical forms to treat these global health problems.

Essential oils (EOs) from the leaves of Artemisia judaica , Ruta graveolens , and Salvia palaestina were analyzed for their phytochemical composition and their antiradical, cytotoxic, and neuromodulatory activities. Using microwave-ultrasonic technology, EOs were extracted from S. palaestina , A. judaica , and R. graveolens , and their antiradical activity (via DPPH assay), cytotoxicity, and neuromodulatory effects (using whole-cell patch-clamp recordings) were evaluated. The main compounds that were explored by GC-MS analysis include piperitone and carvacrol in A. Judaica , 2-undecanone in R. graveolens , and carvacrol in S. palaestina . S. palaestina exhibited the greatest antiradical effect with a 50% inhibition concentration of 8.30 µg/mL. Cytotoxicity tests showed that these EOs express dose-dependent activity on HeLa, HepG3, and B16F1 cancer cells. Among them, S. palaestina and A. judaica were the most potent ones. Patch-clamp recordings showed that S. palaestina was the most potent in inhibiting action toward AMPA receptors, thereby reducing currents up to 6-fold and modulating receptor kinetics. A. Judaica and R. graveolens also inhibited the AMPA receptor activity, but to a lesser extent. These findings point to the important bioactive potential of these EOs, especially S. palaestina , which demonstrated high antiradical and AMPA receptor-modulatory activities and, thus, could be of interest for pharmaceutical and neuroprotective uses.

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.

An optimal balance between excitatory and inhibitory transmission in the central nervous system provides essential neurotransmission for good functioning of the neurons. In the neurology field, a disturbed balance can lead to neurological diseases like epilepsy, Alzheimer’s, and Autism. One of the critical agents mediating excitatory neurotransmission is α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, which are concerned with synaptic plasticity, memory, and learning. An imbalance in neurotransmission finally results in excitotoxicity and neurological pathologies that should be corrected through specific compounds. Hence, the current study will prove to be an evaluation of new thiazole-carboxamide derivatives concerning AMPAR-modulating activity and extended medicinal potential. In the current project, five previously synthesized thiazole-carboxamide derivatives, i.e., TC-1 to TC-5, were used to interact with the AMPARs expressed in HEK293T cells, which overexpress different subunits of the AMPAR. Patch-clamp analysis was carried out while the effect of the drugs on AMPAR-mediated currents was followed with a particular emphasis on the kinetics of inhibition, desensitization, and deactivation. All tested TC compounds, at all subunits, showed potent inhibition of AMPAR-mediated currents, with TC-2 being the most powerful for all subunits. These compounds shifted the receptor kinetics efficiently, mainly enhancing the deactivation rates, and hence acted as a surrogate for their neuroprotective potentials. Additionally, recently published structure–activity relationship studies identified particular substituent groups as necessary for improving the pharmacologic profiles of these compounds. In this regard, thiazole-carboxamide derivatives, particularly those classified as TC-2, have become essential negative allosteric modulators of AMPAR function and potential therapeutics in neurological disturbances underlain by the dysregulation of excitatory neurotransmission. Given their therapeutic effectiveness and safety profiles, these in vivo studies need to be further validated, although computational modeling can be further developed for drug design and selectivity. This will open possibilities for new drug-like AMPAR negative allosteric modulators with applications at the clinical level toward neurology.

Background: Fast excitatory transmission in the central nervous system is carried out by AMPA-type glutamate receptors. Neuronal hyperexcitability and epilepsy have been associated with the dysregulation of AMPA receptor function. Modulation of the gating kinetics of AMPA receptor function has been proposed to be a desirable target for therapy, especially when the modulation is transmembrane AMPA receptor regulatory protein (TARP)-dependent and AMPA receptor subunit composition-dependent. Methods: Eight dibenzobarrelene-based heterocycles were characterized for their effects on the human embryonic kidney cells expressing homomeric GluA1 and heteromeric GluA1/2 AMPA receptors, either alone or co-expressed with the TARPγ8 auxiliary subunit, using whole-cell patch-clamp electrophysiological recordings, and the current amplitude and kinetics of desensitization and deactivation were measured after rapid glutamate application. Results: Each chemical evaluated suppressed glutamate-induced currents via AMPA receptors and augmented both desensitization and deactivation, indicating a negative allosteric modulatory effect. The co-expression of TARPγ8 diminished, but did not eradicate, the inhibition and acceleration induced by the compounds. The observations indicate that the chemicals diminish agonist-bound open states and facilitate transitions to non-conducting states while maintaining effectiveness. Conclusions: The present study describes a specific kinetic mechanism by which dibenzobarrelene derivatives impair the function of the AMPA receptor and its dependence on auxiliary proteins. The present study provides a mechanistic understanding of AMPA receptor gating modulation and establishes a pharmacological framework for future investigations in more physiologically relevant systems.

Isoxazole carboxamide derivatives are intriguing modulators of ionotropic glutamate receptors; more specifically, their prospective analgesic activities based on non-opioid pathways have sparked widespread research. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, especially Ca2+-permeable subtypes that are highly expressed in the spinal dorsal horn, play a critical role in nociceptive transmission and inflammatory pain. Herein, the neuromodulatory effects of these derivatives on AMPA receptor activity have been studied, focusing on their potential as modulators of AMPA receptors, a target implicated in pain and neurological disorders. The whole-cell patch clamp technique for electrophysiological recordings was used to investigate the effect of twelve isoxazole-4-carboxamide derivatives (CIC-1-12) on AMPA receptors’ whole-cell currents and kinetics, including deactivation and desensitization. The isoxazole-4-carboxamide derivatives tested as inhibitors of AMPA receptor activity were very potent, with an 8-fold inhibition by CIC-1 and a 7.8-fold reduction by CIC-2. Additionally, these compounds profoundly altered the biophysical gating properties of both homomeric and heteromeric receptor subunits. These findings emphasize the therapeutic promise of isoxazole-4-carboxamide derivatives due to their potential as AMPA receptor modulators. Their ability to affect receptor activity and gating properties makes them promising candidates for future treatments for controlling pain.

Background Plants have historically been a rich source of medicinal compounds, with many modern pharmaceuticals derived from botanical origins. In contemporary healthcare, there is a resurgence in utilizing botanical substances as recognized medicinal agents. This study delved into understanding the phytochemical makeup and the multifaceted biological activities of an aqueous extract from Cymbopogon citratus ( C. citratus ). The investigated activities were its effect on AMPA receptors, antioxidant capacity, anti-lipase, anti-α-amylase actions, cytotoxicity, and antimicrobial properties. Methods The extract of C. citratus received a comprehensive investigation, which included the study of its phytochemical composition, assessment of its antioxidant and anti-lipase properties, evaluation of its capacity to inhibit α-amylase, analysis of its impact on cell viability, and assessment of its antimicrobial activity. The approaches are used to clarify the complex physiological and biochemical characteristics. Results The results were compelling; receptor kinetics had a marked impact, notably on the GluA2 subunit. Regarding its medicinal potential, the extract demonstrated potent antioxidant and anti-diabetic activities with IC 50 values of 15.13 and 101.14 µg/mL, respectively. Additionally, it displayed significant inhibitory effects on the lipase enzyme and showed cytotoxicity against the Hep3B cancer cell line, with IC 50 values of 144.35 and 148.37 µg/mL. In contrast, its effects on the normal LX-2 cell line were minimal, indicating selectivity. Conclusion The aqueous extract of C. citratus shows promising therapeutic properties. The findings advocate for further research into its compounds for potential isolation, purification, and in-depth pharmacological studies, especially in areas like nervous system disorders, diabetes, obesity, and combating oxidative stress.

Essential oils have been advertised endlessly to be very beneficial for the health of humans, and an extensive amount of research examines the validity of such claims. In contribution, the current study evaluates the neuroprotective properties of Citronellol and Geraniol essential oils (EOs). In relationship to the biophysical gating properties of different the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, the EOs were administered to HEK293 (Human embryonic kidney 293) cells and examined for any inhibition and effect on desensitization or deactivation rates, using whole-cell patch-clamp electrophysiology. Our results demonstrated the highest levels of inhibition from Citronellol oil by four-fold on all AMPARs subunits. Likewise, Geraniol oil had a similar inhibiting impact on the receptors, and both oils decreased the desensitization and deactivation rates of the inhibited receptors. Thus, the examined EOs of this study portray neuroprotective qualities by targeting AMPARs activation and reducing desensitization and deactivation rates. Finally, the results of the current study entail a better understanding of AMPARs, provides a natural template for future drug synthesis to treat neurological diseases associated with excessive AMPAR activation, and offers a possible mechanism by which these essential oils deploy their ‘calming’ effect.

The development of efficacious and safe drugs for the treatment of neurological diseases related to glutamate toxicity has been a focus in neuropharmacological research. Specifically, discovering antagonists to modulate the activity and kinetics of AMPA receptors, which are the fastest ligand-gated ion channels involved in excitatory neurotransmission in response to glutamate. Thus, the current study investigated novel curcumin derivatives on the biophysical properties of AMPA receptors, specifically on the homomeric GluA2 and the heteromeric GluA2/A3 subunits and assessed for inhibitory actions. The biophysical parameter (i.e., desensitization, deactivation, and peak currents) were measured by using whole-cell patch clamp electrophysiology with and without the administration of the derivatives onto HEK293 cells. CR-NN, CR-NNPh, CR-MeNH, and CR-NO of the tested derivatives showed inhibition on all AMPA receptors up to 6 folds. Moreover, the inhibitory derivatives also increased desensitization and deactivation, which further intensifies the compounds' neuroprotective effects. However, CR-PhCl, CR-PhF, and CR-PhBr did not show any significant changes on the peak current, deactivation or desensitization rates. By comparison to other discovered and widely used antagonist, the prepared curcumin derivatives are not selective to a specific AMPA subunit, instead implement its effect in the same way between all types of AMPA receptors. Additionally, the obtained results provide derivatives that not only noncompetitively inhibit AMPARs but also decrease its biophysical kinetics, specifically desensitization and deactivation rates. Hence, to potentially serve as a new AMPAR inhibitor with therapeutic potential, the current study provides compounds that are non-selective and non-competitive antagonist, which also effect the desensitization and deactivation rates of the receptor.

The rising incidence of cancer and the lack of effective therapeutic interventions for many neurological illnesses like Alzheimer's and epilepsy has prompted us to investigate the composition and effects of the Lavandula coronopifolia oil from Palestine on cancer cells and AMPA receptor subunits in the brain due to the vast range of beneficial properties of Lavandula coronopifolia essential oil (EO). GC/MS was used to analyze L. coronopifolia's EO chemistry. EO's cytotoxicity and biophysical effects on AMPA receptors were investigated using MTS and electrophysiological techniques. The GC–MS results revealed that L. coronopifolia EO has a high content of eucalyptol (77.23%), β -pinene (6.93%), and α-pinene (4.95%). The EO showed more significant antiproliferative selectivity activities against HepG2 cancer cell lines than HEK293T cell lines with IC 50 values of 58.51 and 133.22 µg/mL, respectively. The EO of L. coronopifolia affected AMPA receptor kinetics (desensitization and deactivation) and preferred homomeric GluA1 and heteromeric GluA1/A2 receptors. These findings indicate the potential therapeutic use of L. coronopifolia EO in the selective treatment of HepG2 cancer cell lines and neurodegenerative diseases.