2,3-Benzodiazepine compounds are an important family of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists that act in a noncompetitive manner. Due to the critical role of AMPARs in the synapse and various neurological diseases, significant scientific interest in elucidating the molecular basis of the function of the receptors has spiked. The analogues were synthesized to assess the functional consequence of removing the amine group of the phenyl ring, the potency and efficacy of inhibition by substituting a halogen group at the meta vs ortho position of the phenyl ring, and layout the prediction of potential drug candidates for AMPAR hyperactivation. Using the whole-cell patch-clamp technique, we assessed the effect of the derivative on the amplitude of various AMPA-type glutamate receptors and calculated the desensitization and deactivation rates before and after treatment of HEK293 cells. We noticed that the amino group is not necessary for inhibition as long as an electron-withdrawing group is placed on the meta position of the phenyl ring of BDZ. Furthermore, compound 4a significantly inhibited and affected the desensitization rate of the tested AMPARs but showed no effect on the deactivation rate. The current study paves the way to a better understanding of AMPARs and provides possible drug candidates of 2,3-BDZ different from the conventional derivatives.

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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 rise of the emergence of microbial resistance of antibiotics, the dangerous side effects of nonsteroidal anti-inflammatory drugs, and noncompetent medications of Alzheimer’s, Parkinson’s, and other neurodegenerative diseases prompt scientists to search for phytochemicals that could be utilized in the remedy of lethal diseases. Glechoma curviflora (Boiss.) Kuntze (Nepeta curviflora) is a medicinal herb growing in the eastern parts of the Mediterranean Sea Basin and is widely consumed as a tea. The leaves of this plant have been traditionally used for the treatment of various infectious diseases. The current research was designed to identify the chemical composition of Glechoma curviflora (Boiss.) essential oil (EO) and to assess its antibacterial, antifungal, and cyclooxygenase inhibitory activities and the biophysical gating effect on AMPA receptors. Twenty phytochemicals were identified from G. curviflora leaves and flowers EO amounting to almost 100% of the total constituents using GC-MS technique, of which 1,6-dimethylspiro[4.5]decane (27.51%) 1, caryophyllene oxide (20.08%) 2, and β-caryophyllene (18.28%) 3 were the main constituents. The biophysical properties’ effect from the plant extract on various AMPA-type receptors expressed in Human Embryonic Kidney (HEK293) cells was assessed by exploiting the whole-cell patch-clamp technique. Microdilution assay was adopted for assessing the antimicrobial property against eight virulent microbial strains whilst the cyclooxygenase inhibition effect was accomplished utilizing COX inhibitory screening colorimetric assay G. curviflora EO displayed potent activity against P. aeruginosa (MIC = 1.25 μg/mL), S. sonnei (MIC = 3.12 μg/mL), and E. coli (MIC = 1.25 μg/mL), compared with ciprofloxacin (positive control) and potent antibacterial activity against S. aureus, MRSA, S. sonnei, E. coli, and P. aeruginosa compared to Ampicillin (2nd positive control). It also showed anti-Candida (MIC = 6.25 μg/mL) and antimold (MIC = 3.125 μg/mL) activities compared with fluconazole (antifungal positive control). Likewise, our results showed an inhibition and biophysical impact of G. curviflora on all AMPARs subunits.

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