Electronegativity in Substituted-4(H)-quinazolinones Causes Anxiolysis without a Sedative-hypnotic Adverse Reaction in Female Wistar Rats

Author(s): Shweta Mishra, Debashree Das, Adarsh Sahu, Ekta Verma, Shailendra Patil, Ram Kishore Agarwal, Asmita Gajbhiye*

Journal Name: Central Nervous System Agents in Medicinal Chemistry
Formerly Current Medicinal Chemistry - Central Nervous System Agents

Volume 20 , Issue 1 , 2020


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Graphical Abstract:


Abstract:

Objective: In the current study, the synthesis, characterization, and neuropharmacology of quinazolinone tethered with aromatic (3a-3i) and heteroaromatic substitution (3j, 3k, and 3l) as effective anxiolytic agents are reported.

Background: Anxiety and depression are often comorbid with neurological as well as other medical maladies. Clinically known anxiolytics (Benzodiazepines) are accompanied by untoward sedation and other CNS depressive actions. The quinazolinone moiety is a privileged pharmacophore with a wide pharmacological spectrum. Herein, the synthesis, characterization, and neuropharmacological evaluation of some 2-substituted quinazolinone derivatives are reported.

Methods: The synthesized compounds were characterized using 1H-NMR and TLC analysis. Behavioral analysis was performed using EPM (Elevated Plus Maze), OFT (Open Field Test), PIST (Pentobarbital Induced Sleep Test), FST (Forced Swim Test) and PCPA (p-chlorophenyl alanine) bioassay. To further justify the therapeutic claim, systemic and neurotoxicological analysis of the most potent members of the series was performed using OECD mandated protocols. The studies showed that the compounds had a wide therapeutic window with >1000 mg/kg and >500 mg/kg LD50 and NOAEL, respectively.

Results: The compounds with an electronegative group in the quinazolinone nucleus (3f, 3e, 3d, and 3c) induced anxiolysis devoid of sedative adverse reaction. Besides, anti-depressant efficacy of 3f, 3e, 3d, and 3c observed in rodents was a result of a decrease in anxiety level. It was found that the neurotoxicology of the potent members (3f, 3e, 3d, and 3c) advocated their wide therapeutic window with >1000 mg/kg LD50 and >5000 mg/kg NOAEL.

Conclusion: Our findings of behavioral bioassays revealed that inducing an electronegative group into the quinazolinone nucleus yielded the most potent members of the series (3f, 3e, 3d, and 3c). The said compounds were found to produce anxiolysis and anti-depressive action without sedative-hypnotic side effects in rodent models. In summary, it can be stated that extending the studies in a clinical setting would furbish the contours of current anxiolytic therapy, especially in anxiety comorbid with medical maladies.

Keywords: Quinazolinones, anxiolytic, anti-depressant like action, sedative, hypnotic, behavioral studies.

[1]
Alagarsamy, V.; Chitra, K.; Saravanan, G.; Solomon, V.R.; Sulthana, M.T.; Narendhar, B. An overview of quinazolines: Pharmacological significance and recent developments. Eur. J. Med. Chem., 2018, 151, 628-685.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.076] [PMID: 29656203]
[2]
Alenina, N.; Klempin, F. The role of serotonin in adult hippocampal neurogenesis. Behav. Brain Res., 2015, 277, 49-57.
[http://dx.doi.org/10.1016/j.bbr.2014.07.038] [PMID: 25125239]
[3]
Braun, A.A.; Skelton, M.R.; Vorhees, C.V.; Williams, M.T. Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague-Dawley rats: effects of anxiolytic and anxiogenic agents. Pharmacol. Biochem. Behav., 2011, 97(3), 406-415.
[http://dx.doi.org/10.1016/j.pbb.2010.09.013] [PMID: 20869983]
[4]
Clinton-McHarg, T.; Carey, M.; Sanson-Fisher, R.; Tzelepis, F.; Bryant, J.; Williamson, A. Anxiety and depression among haematological cancer patients attending treatment centres: Prevalence and predictors. J. Affect. Disord., 2014, 165, 176-181.
[http://dx.doi.org/10.1016/j.jad.2014.04.072] [PMID: 24882197]
[5]
Colla, A.R.; Rosa, J.M.; Cunha, M.P.; Rodrigues, A.L.S. Anxiolytic-like effects of ursolic acid in mice. Eur. J. Pharmacol., 2015, 758, 171-176.
[http://dx.doi.org/10.1016/j.ejphar.2015.03.077] [PMID: 25861934]
[6]
Dela Peña, I.J.I.; Kim, H.J.; de la Peña, J.B.; Kim, M.; Botanas, C.J.; You, K.Y.; Woo, T.; Lee, Y.S.; Jung, J.C.; Kim, K.M.; Cheong, J.H. A tryptic hydrolysate from bovine milk αs1-casein enhances pentobarbital-induced sleep in mice via the GABAA receptor. Behav. Brain Res., 2016, 313, 184-190.
[http://dx.doi.org/10.1016/j.bbr.2016.07.013] [PMID: 27401107]
[7]
Diniz, T.C.; de Oliveira Júnior, R.G.; Miranda Bezerra Medeiros, M.A.; Gama, E. Silva, M.; de Andrade Teles, R.B.; Dos Passos Menezes, P.; de Sousa, B.M.H.; Abrahão Frank, L.; de Souza Araújo, A.A.; Russo Serafini, M.; Stanisçuaski Guterres, S.; Pereira Nunes, C.E.; Salvador, M.J.; da Silva Almeida, J.R.G. Anticonvulsant, sedative, anxiolytic and antidepressant activities of the essential oil of Annona vepretorum in mice: Involvement of GABAergic and serotonergic systems. Biomed. Pharmacother., 2019, 111, 1074-1087.
[http://dx.doi.org/10.1016/j.biopha.2018.12.114] [PMID: 30841421]
[8]
Feola, B.; Armstrong, K.; Woodward, N.D.; Heckers, S.; Blackford, J.U. Childhood temperament is associated with distress, anxiety and reduced quality of life in schizophrenia spectrum disorders. Psychiatry Res., 2019, 275, 196-203.
[http://dx.doi.org/10.1016/j.psychres.2019.03.016] [PMID: 30925307]
[9]
Gardner, C.R.; Tully, W.R.; Hedgecock, C.J. The rapidly expanding range of neuronal benzodiazepine receptor ligands. Prog. Neurobiol., 1993, 40(1), 1-61.
[http://dx.doi.org/10.1016/0301-0082(93)90047-V] [PMID: 8380934]
[10]
Khan, I.; Tantray, M.A.; Hamid, H.; Alam, M.S.; Kalam, A.; Hussain, F.; Dhulap, A. Synthesis of pyrimidin-4-one-1,2,3-triazole conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity. Bioorg. Chem., 2016, 68, 41-55.
[http://dx.doi.org/10.1016/j.bioorg.2016.07.007] [PMID: 27454617]
[11]
Goel, R.K.; Kumar, V.; Mahajan, M.P. Quinazolines revisited: Search for novel anxiolytic and GABAergic agents. Bioorg. Med. Chem. Lett., 2005, 15(8), 2145-2148.
[http://dx.doi.org/10.1016/j.bmcl.2005.02.023] [PMID: 15808486]
[12]
Harro, J. Animals, anxiety, and anxiety disorders: How to measure anxiety in rodents and why. Behav. Brain Res., 2018, 352, 81-93.
[http://dx.doi.org/10.1016/j.bbr.2017.10.016] [PMID: 29050798]
[13]
McClean, S.; Prosser, E.; Meehan, E.; O’Malley, D.; Clarke, N.; Ramtoola, Z.; Brayden, D. Binding and uptake of biodegradable poly-DL-lactide micro- and nanoparticles in intestinal epithelia. Eur. J. Pharm. Sci., 1998, 6(2), 153-163.
[http://dx.doi.org/10.1016/S0928-0987(97)10007-0] [PMID: 9795038]
[14]
Koss, W.A.; Einat, H.; Schloesser, R.J.; Manji, H.K.; Rubinow, D.R. Estrogen effects on the forced swim test differ in two outbred rat strains. Physiol. Behav., 2012, 106(2), 81-86.
[http://dx.doi.org/10.1016/j.physbeh.2012.01.004] [PMID: 22266677]
[15]
Kuniishi, H.; Ichisaka, S.; Yamamoto, M.; Ikubo, N.; Matsuda, S.; Futora, E.; Harada, R.; Ishihara, K.; Hata, Y. Early deprivation increases high-leaning behavior, a novel anxiety-like behavior, in the open field test in rats. Neurosci. Res., 2017, 123, 27-35.
[http://dx.doi.org/10.1016/j.neures.2017.04.012] [PMID: 28450152]
[16]
Lafioniatis, A.; Bermperian, V.C.; Pitsikas, N. Flumazenil but not bicuculline counteract the impairing effects of anesthetic ketamine on recognition memory in rats. Evidence for a functional interaction between the GABAA-benzodiazepine receptor and ketamine? Neuropharmacology, 2019, 148, 87-95.
[http://dx.doi.org/10.1016/j.neuropharm.2018.12.030] [PMID: 30597159]
[17]
McEown, K.; Treit, D. A2 GABAA receptor sub-units in the ventral hippocampus and α5 GABAA receptor sub-units in the dorsal hippocampus mediate anxiety and fear memory. Neuroscience, 2013, 252, 169-177.
[http://dx.doi.org/10.1016/j.neuroscience.2013.08.012] [PMID: 23962649]
[18]
Sahu, A.; Mishra, S.; Sahu, P.; Gajbhiye, A.; Agrawal, R.K. Indium (III) Chloride: An efficient catalyst for one-pot multicomponent synthesis of 2, 3-dihydroquinazoline-4 (1H)-ones. Curr. Organocatal., 2018, 5(2), 137-144.
[http://dx.doi.org/10.2174/2213337205666180614112318]
[19]
Mulakayala, N.; Kandagatla, B. Ismail; Rapolu, R.K.; Rao, P.; Mulakayala, C.; Kumar, C.S.; Iqbal, J.; Oruganti, S. InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents. Bioorg. Med. Chem. Lett., 2012, 22(15), 5063-5066.
[http://dx.doi.org/10.1016/j.bmcl.2012.06.003] [PMID: 22749421]
[20]
Nilsson, J.; Gidlöf, R.; Nielsen, E.Ø.; Liljefors, T.; Nielsen, M.; Sterner, O. Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors. Bioorg. Med. Chem., 2011, 19(1), 111-121.
[http://dx.doi.org/10.1016/j.bmc.2010.11.050] [PMID: 21163663]
[21]
Pino, E.C.; Zuo, Y.; Borba, C.P.; Henderson, D.C.; Kalesan, B. Clinical depression and anxiety among ST-elevation myocardial infarction hospitalizations: Results from nationwide inpatient sample 2004-2013. Psychiatry Res., 2018, 266, 291-300.
[http://dx.doi.org/10.1016/j.psychres.2018.03.025] [PMID: 29615266]
[22]
Rudolph, U.; Möhler, H. GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annu. Rev. Pharmacol. Toxicol., 2014, 54, 483-507.
[http://dx.doi.org/10.1146/annurev-pharmtox-011613-135947] [PMID: 24160694]
[23]
Sigel, E.; Ernst, M. The benzodiazepine binding sites of GABAA receptors. Trends Pharmacol. Sci., 2018, 39(7), 659-671.
[http://dx.doi.org/10.1016/j.tips.2018.03.006] [PMID: 29716746]
[24]
Solomon, V.R.; Tallapragada, V.J.; Chebib, M.G.A.R. Johnston, and Jane R. Hanrahan. “GABA allosteric modulators: An overview of recent developments in non- benzodiazepine modulators. Eur. J. Med. Chem., 2019. Epub ahead of print
[http://dx.doi.org/10.1016/j.ejmech.2019.03.043]
[25]
Slattery, D.A.; Cryan, J.F. Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat. Protoc., 2012, 7(6), 1009-1014.
[http://dx.doi.org/10.1038/nprot.2012.044] [PMID: 22555240]
[26]
Ulrich-Merzenich, G.; Kelber, O.; Koptina, A.; Freischmidt, A.; Heilmann, J.; Müller, J.; Zeitler, H.; Seidel, M.F.; Ludwig, M.; Heinrich, E.U.; Winterhoff, H. Novel neurological and immunological targets for salicylate-based phytopharmaceuticals and for the anti-depressant imipramine. Phytomedicine, 2012, 19(10), 930-939.
[http://dx.doi.org/10.1016/j.phymed.2012.05.004] [PMID: 22743246]
[27]
Willium David, A.; Lemeke Thomas, A.; Lemeke Thomas, A. Foye’s, W.O. Foye’s principles of medicinal chemistry; Lippincott Williams & Wilkins: Philadelphia, USA, 2008.
[28]
Zhang, C.; Zhao, X.; Mao, X.; Liu, A.; Liu, Z.; Li, X.; Bi, K.; Jia, Y. Pharmacological evaluation of sedative and hypnotic effects of schizandrin through the modification of pentobarbital-induced sleep behaviors in mice. Eur. J. Pharmacol., 2014, 744, 157-163.
[http://dx.doi.org/10.1016/j.ejphar.2014.09.012] [PMID: 25446916]


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Article Details

VOLUME: 20
ISSUE: 1
Year: 2020
Published on: 03 March, 2020
Page: [26 - 40]
Pages: 15
DOI: 10.2174/1871524920666191220112545
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