Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex
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...
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| Format: | Article |
| Language: | English |
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IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund
2023-02-01
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| Series: | EXCLI Journal : Experimental and Clinical Sciences |
| Subjects: | |
| Online Access: | https://www.excli.de/index.php/excli/article/view/5639 |
| _version_ | 1797843497445752832 |
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| author | Elham Rezaee Fatemeh Ahmadi Mahsa Shabaninia Mona Khoramjouy Zahra Azizi Farsani Soraya Shahhosseini Sayyed Abbas Tabatabai Mehrdad Faizi |
| author_facet | Elham Rezaee Fatemeh Ahmadi Mahsa Shabaninia Mona Khoramjouy Zahra Azizi Farsani Soraya Shahhosseini Sayyed Abbas Tabatabai Mehrdad Faizi |
| author_sort | Elham Rezaee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:06:13Z |
| format | Article |
| id | doaj.art-45301b9ec83443fc83427fbbc0a54c96 |
| institution | Directory Open Access Journal |
| issn | 1611-2156 |
| language | English |
| last_indexed | 2024-04-09T17:06:13Z |
| publishDate | 2023-02-01 |
| publisher | IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund |
| record_format | Article |
| series | EXCLI Journal : Experimental and Clinical Sciences |
| spelling | doaj.art-45301b9ec83443fc83427fbbc0a54c962023-04-20T12:35:35ZengIfADo - Leibniz Research Centre for Working Environment and Human Factors, DortmundEXCLI Journal : Experimental and Clinical Sciences1611-21562023-02-012225026210.17179/excli2022-56395078Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complexElham Rezaee0https://orcid.org/0000-0002-6458-0097Fatemeh Ahmadi1https://orcid.org/0000-0001-6946-467XMahsa Shabaninia2Mona Khoramjouy3https://orcid.org/0000-0002-4607-5353Zahra Azizi Farsani4Soraya Shahhosseini5https://orcid.org/0000-0001-5681-073XSayyed Abbas Tabatabai6https://orcid.org/0000-0002-7363-3517Mehrdad Faizi7https://orcid.org/0000-0002-6896-838XDepartment of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, IranPremier Care Long Term Care Pharmacy, North Little Rock, Arkansas, USAPhytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: sa_tabatabai@sbmu.ac.irDepartment of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: m.faizi@sbmu.ac.irAgonists 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.https://www.excli.de/index.php/excli/article/view/5639benzodiazepinebinding assay1,3,4-oxadiazoledockinghypnoticanticonvulsant |
| spellingShingle | Elham Rezaee Fatemeh Ahmadi Mahsa Shabaninia Mona Khoramjouy Zahra Azizi Farsani Soraya Shahhosseini Sayyed Abbas Tabatabai Mehrdad Faizi Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex EXCLI Journal : Experimental and Clinical Sciences benzodiazepine binding assay 1,3,4-oxadiazole docking hypnotic anticonvulsant |
| title | Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex |
| title_full | Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex |
| title_fullStr | Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex |
| title_full_unstemmed | Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex |
| title_short | Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex |
| title_sort | novel 2 substituted 5 4 chloro 2 phenoxy phenyl 1 3 4 oxadiazole derivatives ligands of gabaa benzodiazepine receptor complex |
| topic | benzodiazepine binding assay 1,3,4-oxadiazole docking hypnotic anticonvulsant |
| url | https://www.excli.de/index.php/excli/article/view/5639 |
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