Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex

Design, synthesis, radioligand binding assay, and pharmacological evaluation

Authors

  • Elham Rezaee Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran https://orcid.org/0000-0002-6458-0097
  • Fatemeh Ahmadi Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran https://orcid.org/0000-0001-6946-467X
  • Mahsa Shabaninia Premier Care Long Term Care Pharmacy, North Little Rock, Arkansas, USA
  • Mona Khoramjouy Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran https://orcid.org/0000-0002-4607-5353
  • Zahra Azizi Farsani Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Soraya Shahhosseini Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran https://orcid.org/0000-0001-5681-073X
  • Sayyed Abbas Tabatabai Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: sa_tabatabai@sbmu.ac.ir https://orcid.org/0000-0002-7363-3517
  • Mehrdad Faizi Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: m.faizi@sbmu.ac.ir https://orcid.org/0000-0002-6896-838X

DOI:

https://doi.org/10.17179/excli2022-5639

Keywords:

benzodiazepine, binding assay, 1,3,4-oxadiazole, docking, hypnotic, anticonvulsant

Abstract

Agonists of Benzodiazepine (BZD) receptor are exhaustively used in the control of muscle spasms, seizure, anxiety, and insomnia. BZDs have some unwanted effects; therefore, the development of new BZD receptor agonists with better efficacy and fewer unwanted effects is one of the subjects of interest. In this study, based on the pharmacophore/receptor model of the BZD binding site of GABAA receptors, a series of new 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives (6a-f) were designed. Energy minima conformers of the designed compounds and diazepam were well matched in conformational analysis and showed proper interaction with the BZD-binding site of the GABAA receptor model (α1β2ϒ2) in docking studies. The designed compounds were synthesized in acceptable yield and evaluated for their in vitro affinity to the benzodiazepine receptor of rat brains by radioligand receptor binding assay. The results demonstrated that the affinities of most of the novel compounds were even higher than diazepam. The novel compound 6a with the best affinity in radioligand receptor binding assay (Ki=0.44 nM and IC50= 0.73±0.17 nM) had considerable hypnotic activity and weak anticonvulsant and anxiolytic effects with no negative effect on memory in animal models. Flumazenil as a selective benzodiazepine receptor antagonist was able to prevent hypnotic and anticonvulsant effects of 6a indicating the role of BZD receptors in these effects.

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Published

2023-02-20

How to Cite

Rezaee, E., Ahmadi, F., Shabaninia , M., Khoramjouy, M., Azizi Farsani, Z., Shahhosseini, S., … Faizi, M. (2023). Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex: Design, synthesis, radioligand binding assay, and pharmacological evaluation. EXCLI Journal, 22, 250–262. https://doi.org/10.17179/excli2022-5639

Issue

Vol. 22 (2023)

Section

Original articles

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Copyright (c) 2023 Elham Rezaee, Fatemeh Ahmadi, Mahsa Shabaninia , Mona Khoramjouy, Zahra Azizi Farsani, Soraya Shahhosseini, Sayyed Abbas Tabatabai, Mehrdad Faizi

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