Ortho versus Meta Chlorophenyl-2,3-Benzodiazepine Analogues: Synthesis, Molecular Modeling, and Biological Activity as AMPAR Antagonists

Abstract

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.

New psychoactive substances: a review and updates

“…Tofisopam is a competitive antagonist at this receptor (and doesn't have GABA-A activity) and may cause anxiolytic actions without the sedative effects seen with other benzodiazepines. 184 Harms and adverse effects. Data on the effects and harms of new synthetic benzodiazepines remains somewhat limited at this time, but early studies have shown anxiolytic, anticancer, anticonvulsant, antipsychotic, muscle relaxant, antituberculosis and antimicrobial actions.…”

“…Data on the effects and harms of new synthetic benzodiazepines remains somewhat limited at this time, but early studies have shown anxiolytic, anticancer, anticonvulsant, antipsychotic, muscle relaxant, antituberculosis and antimicrobial actions. 179,185 Adverse effects include a sedative-hypnotic toxidrome and can include confusion, dizziness, drowsiness fatigue, as well as auditory and visual hallucinations, delirium, seizures, deep sleep and coma, 184 and atypical symptoms such as agitation, hyperthermia and tachycardia. 186 Abrupt cessation may lead to withdrawal symptoms, such as anxiety, panic attacks, restlessness, insomnia and convulsions.…”

Design, synthesis and biological evaluation of novel benzodioxole derivatives as COX inhibitors and cytotoxic agents

“…The methyl 3,4-(methylenedioxy) phenylacetate (2) was generated by an esterification reaction of 3,4-(methylenedioxy) phenylacetic acid (1). To produce the ester (2), oxalyl chloride was added dropwise to methanol solvent and stirred for half an hour in an ice bath [33,34]. The IR spectra of the ester (2) showed the disappearance of the broad band that belonged to the acetic acid group of (1).…”

Synthesis and Biological Evaluation of Benzodioxole Derivatives as Potential Anticancer and Antioxidant agents

“…According to the 13 C-NMR spectrum, C signal of carbonyl groups was found at 194 and 171 ppm for 5a, and at 37-51 ppm two signals of aliphatic carbon were observed, and similar signals for 5b were observed. The subsequent treatment of ketoester (5a & 5b) with hydrazine hydrate in ethanol with acetic acid afforded the benzodiazepine derivatives 7a and 7b [24], compounds 6a & 6b were synthesized by hydrolysis reaction of the ester compounds 5a & 5b using LiOH [38]. (see Scheme 1).…”

“…Therefore, benzodiazepine (BDZs) derived molecules have various biological and pharmacological effects. In addition to their effect on the central nervous system [23,24], they also have anti-proliferative activities [25], anti-HIV [26], anti-inflammatory [27] and anti-microbial activities [28]. While the compounds containing benzodioxole e moiety have been shown to have different biological activity including anticancer, anti-tuberculosis, antimicrobial, analgesic, and anti-epileptic activities ( Figure 3) [29][30][31][32][33][34].…”