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Synthesis and Influence of Two Quinoxalinone Derivatives on Anxiety- and Depressive-Like Responses in Wistar Rat

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DOI: 10.4236/nm.2012.34039    3,924 Downloads   6,106 Views   Citations


Two new quinoxalinone derivatives have been synthesized adopting the HONG method, and investigated for some neuropharmacological effects (anxiety- and depressive-like responses) in rats. The present experiment sought to determine whether treatment with these compounds produces changes in affective responses. We found that the chronic injection of 6-nitro-2(1H)-quinoxalinone (NQu) showed obvious anxiolytic- and antidepressant-like effects, respectively, measured in the behavioral tests of Elevated Plus Maze (EPM) and Forced Swim Test (FST). At the dose of 30 mg/kg, NQu showed a comparative anxiolytic-like effect in rats as diazepam (Dz) (1 mg/kg), and a comparative antidepressant effect as clomipramine (Clmp) (2 mg/kg; i.p). The 2(1H)-quinoxalinone (Qu) significantly reduced depressive-like responses as evaluated in FST, whereas no anxiolytic-like effect was found as measured by open field test (OF). Additionally, the locomotor activity levels were unaffected by treatment as measured by OF and EPM.

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R. Nakache, B. Lakhrissi, F. Mrabet, A. Elhessni, A. Ouichou, B. Benazzouz and A. Mesfioui, "Synthesis and Influence of Two Quinoxalinone Derivatives on Anxiety- and Depressive-Like Responses in Wistar Rat," Neuroscience and Medicine, Vol. 3 No. 4, 2012, pp. 330-336. doi: 10.4236/nm.2012.34039.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] M. M. Badran, K. A. M Abouzid, M. H. M. Hussein, “Synthesis of Certain Substituted Quinoxalines as Anti- Microbial Agents, Part II,” Archives of Pharmacal Research, Vol. 26, No. 2, 2003, pp. 107-113. doi:10.1007/BF02976653
[2] A. A. El-Gendy, S. El-Meligie, A. El-Ansary and A. M. Ahmedy, “Synthesis of Some Quinoxaline Derivatives Containing Indoline-2,3-Dione or Thiazolidine Residue as Potential Antimicrobial Agents,” Archives of Pharmacal Research, Vol. 18, No. 1, 1995, pp. 44-47. doi:10.1007/BF02976507
[3] S. A. El-Hawash, N. S. Habib and N. H. Fanaki, “Quinoxaline Derivatives Part II: Synthesis and Antimicrobial testing of 1,2,4-Triazolo[4,3-α]quinoxalines, 1,2,4-Triazino[4,3-α]-quinoxalines and 2-Pyrazolylquino-Xa-Lines,” Pharmazie, Vol. 54, No. 11, 1999, pp. 808-815.
[4] M. N. A. Nasr, “Synthesis and Antibacterial Activity of Fused 1,2,4-Triazolo[4,3-α]quinoxaline and Oxopyrimido[2’,1’:5,1]-1,2,4-triazolo[4,3-α]-quinoxaline Derivatives,” Archiv der Pharmazie, Vol. 8, No. 8, 2002, pp. 389-394. doi:10.1002/1521-4184(200211)335:8<389::AID-ARDP389>3.0.CO;2-X
[5] H. M. Refaat, A. A. Moneer and O. M. Khalil, “Synthesis and Antimicrobial Activity of Certain Novel Quinoxalines,” Archives of Pharmacal Research, Vol. 27, No. 11, 2004, pp. 1093-1098. doi:10.1007/BF02975110
[6] Y. Kurasawa, M. Muramatsu, K. Yamazaki, S. Tajima, Y. Okamoto and A. Takada, “A Facile Synthesis of 1-Aryl- 3-heteroaryl-1H-pyrazolo[3,4-6]quinoxalines and Related Compounds with Antifungal Activity,” Journal of Heterocyclic Chemistry, Vol. 23, No. 5, 1986, pp. 1391-1394. doi:10.1002/jhet.5570230527
[7] P. Sanna, A. Carta, M. Loriga, S. Zanetti and L. Sechi, “Synthesis of 3,6,7-Substituted-Quinoxalin-2-Ones for Evaluation of Antimicrobial and Anticancer Activity Part 2,” Il Farmaco, Vol. 54, No. 3, 1999, pp. 161-168. doi:10.1016/S0014-827X(99)00010-5
[8] A. Carta, P. Sanna, L. Gherardini, D. Usai and S. Zanetti, “Novel Functionalized Pyrido[2,3-9]Quinoxalinones as Antibacterial, Antifungal and Anticancer Agents,” Il Farmaco, Vol. 56, No. 12, 2001, pp. 933-938. doi:10.1016/S0014-827X(01)01161-2
[9] A. Monge, F. J. Martinez-Crespo, A. L. Cerain, J. A. Palop, S. Narro, V. Senador, A. Marin, Y. Sainz, M. Gonzalez, E. Hamilton and A. J. Barker, “Hypoxia-Selective Agents Derived from 2-Quinoxaline Carbonitrile 1,2-Di-N-Oxides,” Journal of Medicinal Chemistry, Vol. 38, No. 22, 1995, pp. 4488-4494. doi:10.1021/jm00022a014
[10] A. F. Crowther, F. H. S. Curd, D. G. Davey and G. J. Stacey, “Synthetic Antimalarials. Part XXXIX,” Journal of the Chemical Society, 1949, pp. 1260-1262. doi:10.1039/jr9490001260
[11] J. B. Rangisetty, C. N. V. H. B. Gupta, A. L. Prasad, P. Srinivas, N. Sridhar, P. Parimoo and A. Veeranjaneyulu “Synthesis of New Arylaminoquinoxalines and Their Antimalarial Activity in Mice,” Journal of Pharmacy and Pharmacology, Vol. 53, No. 10, 2001, pp. 1409-1413.
[12] A. Jaso, B. Zarranz, I. Aldana and A. Monge, “Synthesis of New 2-Acetyl and 2-Benzoylquinoxaline 1,4-Di-N- Oxide Derivatives as Anti-Mycobacterium tuberculosis Agents,” European Journal of Medicinal Chemistry, Vol. 38, No. 9, 2003, pp. 791-800. doi:10.1016/S0223-5234(03)00137-5
[13] R. Sarges, H. R. Howard, R. G. Browne, L. A. Lebel, P. A. Seymour and B. K. Koe, “4-Amino[1,2,4]triazolo[4,3- a]quinoxalines. A Novel Class of Potent Adenosine Receptor Antagonists and Potential Rapid-Onset Antidepressants,” Journal of Medicinal Chemistry, Vol. 33, No. 8, 1990, pp. 2240-2254. doi:10.1021/jm00170a031
[14] S. Keslacy, O. Tliba, H. Baidouri and Y. Amrani, “Inhibition of Tumor Necrosis Factor-α-Inducible Inflammatory Genes by Interferon-γ Is Associated with Altered Nuclear Factor-κB Transactivation and Enhanced Histone Deacetylase Activity,” Molecular Pharmacology, Vol. 71, No. 2, 2007, pp. 609-618. doi:10.1124/mol.106.030171
[15] D.-S. Su, M. K. Markowitz, R. M. DiPardo, K. L. Murphy, C. M. Harrell, S. S. O’Malley, R. W. Ransom, R. S. L. Chang, S. Ha, F. J. Hess, D. J. Pettibone, G. S. Mason, S. Boyce, R. M. Freidinger and M. G. Bock, “Discovery of a Potent, Non-peptide Bradykinin B1 Receptor Antagonist,” Journal of the American Chemical Society, Vol. 125, No. 25, 2003, p. 7516. doi:10.1021/ja0353457
[16] R. E. TenBrink, W. B. Im, V. H. Sethy, A. H. Tang and D. B. Carter, “Antagonist, Partial Agonist, and Full Agonist Imidazo[1,5-α]Quinoxaline Amides and Carbamates Acting through the GABAA/Benzodiazepine Receptor,” Journal of Medicinal Chemistry, Vol. 37, No. 6, 1994, pp. 758-768. doi:10.1021/jm00032a008
[17] M. Abou-Gharbia, M. E. Freed, R. J. McCaully, P. J. Silver and R. L. J. Wendt, “Tetrahydropyrrolo[1,2-α]quinoxalines and Tetrahydropyrrolo[1,2-α]pyrido[3,2-α]pyrazines: Vascular Smooth Muscle Relaxants and Antihypertensive Agents,” Journal of Medicinal Chemistry, Vol. 27, No. 12, 1984, pp. 17-43. doi:10.1021/jm00378a039
[18] B. Meldrum, “Protection Against Ischaemic Neuronal Damage by Drugs Acting on Excitatory Transmission,” Cerebrovascular & Brain Metabolism Reviews, Vol. 2, No. 1, 1990, pp. 27-57.
[19] M. J. Croucher, J. F. Collins, and B. S. Meldrum, “Anticonvulsant Action of Excitatory Amino Acid Antagonists,” Science, Vol. 216, No. 4548, 1982, pp. 899-901. doi:10.1126/science.7079744
[20] A. J. Milnerwood, C. M. Gladding, M. A. Pouladi, A. M. Kaufman, R. M. Hines, J. D. Boyd, R. W.Y. Ko, O. C. Vasuta, R. K. Graham, M. R. Hayden, T. H. Murphy and L. A. Raymondl, “Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington’s Disease Mice,” Neuron, Vol. 65, 2010, pp. 178-190. doi:10.1016/j.neuron.2010.01.008
[21] J. C. Randle, T. Guet, C. Bobichon, C. Moreau, P. Curutchet, B. Lambolez, L. P. de Carvalho, A. Cordi and J. M. Lepagnol, “Quinoxaline Derivatives: Structure-Activity Relationships and Physiological Implications of Inhibition of N-Methyl-D-Aspartate and Non-N-Methyl-D-Aspartate Receptor-Mediated Currents and Synaptic Potentials,” Molecular Pharmacology, Vol. 41, No. 2, 1992, pp. 337-345.
[22] J. C. R. Randle, T. Guet, A. Cordi and J. M. Lepagnol, “Competitive Inhibition by NBQX of Kainate/AMPA Receptor Currents and Excitatory Synaptic Potentials: Importance of 6-Nitro Substitution,” European Journal of Pharmacology, Vol. 215, No. 2-3, 1992, pp. 237-244. doi:10.1016/0014-2999(92)90033-Z
[23] W. Loscher, “New Visions in the Pharmacology of Anticonvulsion,” European Journal of Pharmacology, Vol. 342, No. 1, 1998, pp. 1-13. doi:10.1016/S0014-2999(97)01514-8
[24] M. A. Rogawski and S. D. Donevan, “AMPA Receptors in Epilepsy and as Targets for Antiepileptic Drugs,” Advances in Neurology, Vol. 79, 1999, pp. 947-963.
[25] S. Maeng, C. A. Zarate Jr., J. Du, R. J. Schloesser, J. Mc-Cammon, G. Chen and H. K. Manji, “Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptors,” Biological Psychiatry, Vol. 63, No. 4, 2008, pp. 349-352. doi:10.1016/j.biopsych.2007.05.028
[26] A. Chimirri, R. Gitto and M. Zappala, “AMPA Receptor Antagonists,” Expert Opinion on Therapeutic Patents, Vol. 9, No. 5, 1999, pp. 557-570. doi:10.1517/13543776.9.5.557
[27] G. Olayiwola, C. A. Obafemi and F. O. Taiwo, “Synthesis and Neuropharmacological Activity of Some Quinoxalinone Derivatives,” African Journal of Biotechnology, Vol. 6, No. 6, 2007, pp. 777-786.
[28] T. Honore, S. N. Davis, J. Drejer, E. J. Flecher, P. Jacobsen, D. Lodge and F. E. Nielson, “Quinoxalinediones: Potent Competitive Non-NMDA Glutamate Receptor Antagonists,” Science, Vol. 241, No. 4866, 1988, pp. 701-703. doi:10.1126/science.2899909
[29] P. J. Birch, C. J. Grossman and A. G. Hayes, “6,7-Dinitro-quinoxaline-2,3-dion and 6-Nitro,7-cyanoquinoxaline- 2,3-dion antagonise Responses to NMDA in the Rat Spinal Cord via an Action at the Strychnine-Insensitive Glycine Receptor,” European Journal of Pharmacology, Vol. 156, No. 1, 1988, pp. 177-180. doi:10.1016/0014-2999(88)90163-X
[30] A. Grandson, J. Drejer and A. Schousboe, “Direct Evidence that Excitotoxicity in Cultured Neurons Is Mediated via N-Methyl-D-Aspartate (NMDA) as Well as Non-NMDA Receptors,” Journal of Neurochemistry, Vol. 53, No. 1, 1989, pp. 297-299. doi:10.1111/j.1471-4159.1989.tb07327.x
[31] M. J. Sbeardown, E. O. Nielsen, A. J. Hansen, P. Jacobseq and T. Honoré, “2,3-Dihydroxy-6-nitro-7-sulfa-moyl-benzo(F)quinoxaline: A Neuroprotectant for Cerebral Ischemia,” Science, Vol. 247, No. 4942, 1990, pp. 571-574. doi:10.1126/science.2154034
[32] Y. S. Hong, H. M. Kim, Y. T. Park and H. S. Kim, “Heterocyclic Compounds with Sulfone Functional Groups (II): Synthesis of 1-Arenesulfonyl-2-Quinoxalinones,” Bulletin of the Korean Chemical Society, Vol. 21, No. 1, 2000, pp. 133-136.
[33] J. N. Crawley, “What’s Wrong with My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice,” John Wiley & Sons, Inc., New York, 2000, p. 95.
[34] A. Ramos, O. Berton, P. Mormede and F. Chaouloff, “A multiple Test Study of Anxiety Related Behaviours in Six Inbred Rat Strains,” Behavioural Brain Research, Vol. 85, No. 1, 1997. pp. 57-69. doi:10.1016/S0166-4328(96)00164-7
[35] S. Pellow, P. Chopin, S. E. File and M. Briley, “Validation of Open: closed Arm Entries in an Elevated Plus- Maze as a Measure of Anxiety in the Rat,” Journal of Neuroscience Methods, Vol. 14, No. 3, 1985, pp. 149-167. doi:10.1016/0165-0270(85)90031-7
[36] R. E. Brown, S. Corey and A. K. Moore, “Differences in Measures of Exploration and Fear in MHC-Congenic C57BL/6J and B6-H-2K Mice”. Behavior Genetics, Vol. 26, No. 4, 1999, pp. 263-271. doi:10.1023/A:1021694307672
[37] R. G. Lister, “The Use of a Plus-Maze to Measure Anxiety in the Mouse,” Psychopharmacology, Vol. 111, 1987, pp. 323-331.
[38] R. Trullas and P. Skolnick, “Differences in Fear Motivated Behaviour among In-Bred Mouse Strains,” Psychopharmacology, Vol. 111, No. 3, 1993, pp. 323-331. doi:10.1007/BF02244948
[39] R. D. Porsolt, A. Bertin and M. Jalfre, “Behavioral Despair in Mice: A Primary Screening Test for Antidepressants,” Archives Internationales de Pharmacodynamie et de Therapie, Vol. 229, No. 2, 1977, pp. 327-336.
[40] G. Griebel, C. Belzung, G. Perrault and D. J. Sanger, “Differences in Anxiety-Related Behaviours and in Sensitivity to Diazepam in Inbred and Outbred Strains of Mice,” Psychopharmacology, Vol. 148, No. 2, 2000, pp. 164-170. doi:10.1007/s002130050038

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