NM  Vol.3 No.4 , December 2012
Synthesis and Influence of Two Quinoxalinone Derivatives on Anxiety- and Depressive-Like Responses in Wistar Rat
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.

Cite this paper
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.
[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