Novel Derivatives of diphenyl-1,3,4-oxadiazol as Ligands of Benzodiazepine Receptors; Synthesize, Binding Assay and Pharmacological Evaluation

Document Type : Research article

Authors

1 Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 bPhytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Department of Pharmaceutical Chemistry and Radiopharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

4 School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

5 Protein Technology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

10.22037/ijpr.2021.115549.15429

Abstract

Benzodiazepines (BZD) are among the main classes of tranquilizing drugs, bearing much less toxicity compared to other drugs acting on the CNS. Considering the pharmacophore model of BZD binding to GABA-A receptor, novel diphenyl 1,3,4-oxadiazole compounds as BZD ligands were designed. The compounds were synthesized and structurally confirmed using LCMS, IR and NMR techniques. We investigated the affinity of the compounds to BZD receptors using radioligand [3H]-flumazenil by in-vitro studies. In addition, sedative-hypnotic, anxiety, anticonvulsant, muscle relaxant, memory impairment, and motor coordination activities of the synthesized compounds were evaluated using in-vivo studies. Based on in-vitro studies, compounds 7i and 7j were the most potent with IC50 values of 1.54 and 1.66 nM respectively. In-vivo studies showed that compound 7i has the highest impact on increased sedation, muscle relaxation, and decreased anxiety and these observations were antagonized by flumazenil. Compounds 7e and 7i were the most potent anticonvulsant agents among synthesized compounds in both MES and PTZ induced seizure tests. All synthesized compounds significantly decreased latency to fall in the Rotarod test but none of them had a significant impact on the memory impairment test.  

Graphical Abstract

Novel Derivatives of diphenyl-1,3,4-oxadiazol as Ligands of Benzodiazepine Receptors; Synthesize, Binding Assay and Pharmacological Evaluation

Keywords


(1)      Filizola M, Harris DL and Loew GH. Development of a 3D pharmacophore for nonspecific ligand recognition of α1, α2, α3, α5, and α6 containing gaba A /benzodiazepine receptors. Bioorg. Med. Chem. (2000) 8: 1799–807.
(2)      O’Donnell SB, Nicholson MK and Boland JW. The association between benzodiazepines and survival in patients with cancer: a systematic review. J. Pain. Symptom. Manage. (2019) 57: 999-1008.
(3)      Marangos PJ and Martino AM. Studies on the relationship of gamma-aminobutyric acid-stimulated diazepam binding and the gamma-aminobutyric acid receptor. Mol. Pharmacol. (1981) 20: 16–21.
(4)      Cornett EM, Novitch MB, Brunk AJ, Davidson KS, Menard BL, Urman RD and Kaye AD. New benzodiazepines for sedation. Best. Pract. Res. Clin. Anaesthesiol. (2018) 32: 149–64.
(5)      Kelly MD, Smith A, Banks G, Wingrove P, Whiting PW, Atack J, Seabrook GR and Maubach KA. Role of the histidine residue at position 105 in the human α5 containing GABA A receptor on the affinity and efficacy of benzodiazepine site ligands. Br. J. Pharmacol. (2002) 135: 248–56.
(6)      Nilsson J, Østergaard Nielsen E, Liljefors T, Nielsen M and Sterner O. 3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors. Bioorg. Chem. (2012) 40: 125–30.
(7)      Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B and Shafiee A. Design and synthesis of 4H-3-(2-Phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists. Bioorg. Med. Chem. (2003) 11: 769–73.
(8)      Lager E, Nilsson J, Østergaard Nielsen E, Nielsen M, Liljefors T and Sterner O. Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors. Bioorg. Med. Chem. (2008) 16: 6936–48.
(9)      Sigel E and Ernst M. The Benzodiazepine Binding Sites of GABAA Receptors. Trends Pharmacol. Sci. (2018) 39: 659–71.
(10)    Bigott-Hennkens HM, Dannoon S, Lewis MR and Jurisson SS. In vitro receptor binding assays: general methods and considerations. Q. J. Nucl. Med. Mol. Imaging. (2008) 52: 245–53.
(11)    Chebib M and Johnston GAR. The “abc” of gaba receptors: a brief review. Clin. Exp. Pharmacol. Physiol. (1999) 26: 937–40.
(12)    Griffin CE, Kaye AM, Bueno FR and Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner. J. (2013) 13: 214–23.
(13)    Carling RW, Moore KW, Street LJ, Wild D, Isted C, Leeson PD, Thomas S, O'Connor D, McKernan RM, Quirk K, Cook SM, Atack JR, Wafford KA, Thompson SA, Dawson GR, Ferris P and Castro JL. 3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4- a ]phthalazines and Analogues: High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1. J. Med. Chem. (2004) 47: 1807–22.
(14)    Selleri S, Gratteri P, Costagli C, Bonaccini C, Costanzo A, Melani F, Guerrini G, Ciciani G, Costa B, Spinetti F, Martini C and Bruni F. Insight into 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as peripheral benzodiazepine receptor ligands: Synthesis, biological evaluation and 3D-QSAR investigation. Bioorg. Med. Chem. (2005) 13: 4821–34.
(15)    Tabatabai SA, Rezaee Zavareh E, Reyhanfard H, Alinezhad B, Shafaghi B, Sheikhha M, Shafiee A and Faizi M. Evaluation of anxiolytic, sedative-hypnotic and amnesic effects of novel 2-phenoxy phenyl-1,3,4-oxadizole derivatives using experimental models. Iran. J. Pharm. Res. (2015) 14: 51–7.
(16)    Neumeyer JL, Baindur N, Yuan J, Booth G, Seeman P and Niznik HB. Development of a high affinity and stereoselective photoaffinity label for the D-1 dopamine receptor: synthesis and resolution of 7-[125I]iodo-8-hydroxy-3-methyl-1-(4’-azidophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine. J. Med. Chem. (1990) 33: 521–6.
(17)    Zarghi A, Tabatabai SA, Faizi M, Ahadian A, Navabi P, Zanganeh V and Shafiee A. Synthesis and anticonvulsant activity of new 2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles. Bioorg. Med. Chem. Lett. (2005) 15: 1863–5.
(18)    Almasirad A, Tabatabai SA, Faizi M, Kebriaeezadeh A, Mehrabi N, Dalvandi A and Shafiee A. Synthesis and anticonvulsant activity of new 2-substituted-5- [2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg. Med. Chem. Lett. (2004) 14: 6057–9.
(19)    Zarghi A, Hajimahdi Z, Mohebbi S, Rashidi H, Mozaffari S, Sarraf S, Faizi M, Tabatabi SA and Shafiee A. Design and synthesis of new 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as anticonvulsant agents. Chem. Pharm. Bull. (2008) 56: 509–12.
(20)    Zarghi A, Hamedi S, Tootooni F, Amini B, Sharifi B, Faizi M, Tabatabai SA and Shafiee A. Synthesis and pharmacological evaluation of new 2-substituted-5-{2-[(2-halobenzyl)thio)phenyl}-1,3,4-oxadiazoles as anticonvulsant agents. Sci. Pharm. (2008) 76: 185–201.
(21)    Ahmadi F, Dabirian S, Faizi M, Tabatabai SA, Beiki D and Shahhosseini S. Optimum conditions of radioligand receptor binding assay of ligands of benzodiazepine receptors. Iran. J. Pharm. Res. (2014) 13: 79–86.
(22)    Bylund DB and Toews ML. Radioligand binding methods: practical guide and tips. Am. J. Physiol. Cell. Mol. Physiol. (1993) 265: L421–9.
(23)    Qume M. Overview of ligand-receptor binding techniques. In: Receptor Binding Techniques. Methods. Mol. Biol. (1999) 106: 3-23.
(24)    Seibenhener ML, Wooten MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J. Vis. Exp. (2015) 96: e52434.
(25)    Suleyman H, Guvenalp Z, Kizilkaya M and Demirezer Lo. Sedative effect of centranthus longiflorus ssp. longiflorus in rats and the influence of adrenalectomy on its effect. Yakugaku zasshi. (2007) 127: 1263–5.
(26)    Shi R, Han Y, Yan Y, Qiao H-Y, He J, Lian WW, Xia CY, Ting-Li L, Zhang WK and Xu JK. Loganin exerts sedative and hypnotic effects via modulation of the serotonergic system and GABAergic neurons. Front. Pharmacol. (2019) 10: 409.
(27)    Carola V, D’Olimpio F, Brunamonti E, Mangia F and Renzi P. Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behav. Brain. Res. (2002) 134: 49–57.
(28)    Holmes A and Rodgers RJ. Influence of spatial and temporal manipulations on the anxiolytic efficacy of chlordiazepoxide in mice previously exposed to the elevated plus-maze. Neurosci. Biobehav. Rev. (1999) 23: 971–80.
(29)    Bachstetter AD, Webster SJ, Tu T, Goulding DS, Haiech J, Watterson DM and Van Eldik AJ. Generation and behavior characterization of CaMKIIβ knockout mice. PLoS One (2014) 9: e105191.
(30)    Faizi M, Sheikhha M, Ahangar N, Tabatabaei Ghomi H, Shafaghi B, Shafiee A and Tabatabai SA. Design, synthesis and pharmacological evaluation of novel 2-[2-(2-chlorophenoxy) phenyl]-1,3,4-oxadiazole derivatives as benzodiazepine receptor agonists. Iran. J. Pharm. Res. (2012) 11: 83–90.
(31)    Ranjbar Ekbatan M, Khoramjouy M, Gholamine B, Faizi M and Sahranavard S. Evaluation of anticonvulsant effect of aqueous and methanolic extracts of seven Inula species. Iran. J. Pharm. Res. (2019) 18: 208–20.
(32)    Bienvenu E, Amabeoku GJ, Eagles PK, Scott G and Springfield EP. Anticonvulsant activity of aqueous extract of Leonotis leonurus. Phytomedicine. (2002) 9: 217–23.
(33)    Luszczki JJ, Andres MM, Czuczwar P, Cioczek-Czuczwar A, Wojcik-Cwikla J, Ratnaraj N, Patsalos PN and Czuczwar SJ. Levetiracetam selectively potentiates the acute neurotoxic effects of topiramate and carbamazepine in the rotarod test in mice. Eur. Neuropsychopharmacol. (2005) 15: 609–16.
(34)    Peña I dela, Yoon SY, Kim HJ, Park S, Hong EY, Ryu JH, Park IH and Cheong JH. Effects of ginseol k-g3, an Rg3-enriched fraction, on scopolamine-induced memory impairment and learning deficit in mice. J. Ginseng. Res. (2014) 38: 1–7.
(35)  Khoramjouy M, Rezaee E, Khoshnevis A, Nazari M, Nematpour M, Shahhosseini S, Tabatabai SA and Faizi M. Synthesis of 4,6-diphenylpyrimidin-2-ol derivatives as new benzodiazepine receptor ligands. Bioorg. Chem. (2021) 109: 104737.