Synthesis and Evaluation of Anticonvulsant Activity of 6,8-Dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline in PTZ-Induced Seizure Model in Mice


This study we describe the synthesis of a novel structure of anticonvulsant agent as 6,8-dimethoxy-3-methyl-1,2,3,4- tetrahydroisoquinoline by using GYKI52466, which was the potent anticonvulsant agent, as the lead molecule. Com-pound IV was synthesized and anticonvulsant effects was evaluated against Pentylenetetrazole (PTZ)-induced seizure model in mice. The acute anticonvulsant effect was tested with a single dose of 25 and 75 µmol/kg of the synthesis compound. Sodium valproate and normal saline were used as the reference standard and control, respectively. All compounds were injected intraperitoneally to each mouse an hour prior to seizure induced by injection of 60 mg/kg PTZ and observed their behavior for 30 minutes. The result showed that the IV at 75 µmol/kg could delay the latency to first twitch and decrease percent mortality compared to control group.

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Y. Pariyawongsakul, C. Patarapanich, C. Boonyarat and P. Puthongking, "Synthesis and Evaluation of Anticonvulsant Activity of 6,8-Dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline in PTZ-Induced Seizure Model in Mice," Open Journal of Medicinal Chemistry, Vol. 2 No. 3, 2012, pp. 72-77. doi: 10.4236/ojmc.2012.23009.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] R. S. Fisher, W. van Emde Boas, W. Blume, C. Elger, P. Genton, P. Lee and J. J. Engel, “Epileptic Seizures and Epilepsy: Definitions Proposed by the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE),” Epilepsia, Vol. 46, No. 4, 2005, pp. 470472. doi:10.1111/j.0013-9580.2005.66104.x
[2] A. C. Gerlach and J. L. Krajewski, “Antiepileptic Drug Discovery and Development: What Have We Learned and Where Are We Going?” Pharmaceuticals, Vol. 3, No. 9, 2010, pp. 2884-2899. doi:10.3390/ph3092884
[3] A. Chimirri, G. De Sarro, A. De Sarro, R. Gitto, S. Grasso, S. Quartarone, M. Zappalà, P. Giusti, V. Libri, A. Constanti and A. G. Chapman, “1-Aryl-3,5-dihydro4H-2,3-benzodiazepin-4-ones: Novel AMPA Receptor Antagonists,” Journal of Medicinal Chemistry, Vol. 40, No. 8, 1997, pp. 1258-1269. doi:10.1021/jm960506l
[4] A. Chimirri, G. De Sarro, A. De Sarro, R. Gitto , S. Quartarone, M. Zappalà, A. Constanti and V. Libri, “3,5Dihydro-4H-2,3-benzodiazepine-4-thiones: A New Class of AMPA Receptor Antagonists,” Journal of Medicinal Chemistry , Vol. 41, No. 18, 1998, pp. 3409-3416. doi:10.1021/jm9800393
[5] M. Zappalà, R. Gitto, F. Bevacqua, S. Quartarone, A. Chimirri, M. Rizzo, G. D. Sarro and A. D. Sarro, “Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of 11H-[1,2,4]triazolo[4,5-c][2,3] benzodiazepin-3(2H)-ones,” Journal of Medicinal Chemistry, Vol. 43, No. 25, 2000, pp. 4834-4839. doi:10.1021/jm001012y
[6] M. Zappalà, G. Postorino, N. Micale, S. Caccamese, N. Parrinello, G. Grazioso, G. Roda, F. S. Menniti, G. D. Sarro and S. Grasso, “Synthesis, Chiral Resolution, and Enantiopharmacology of a Potent 2,3-Benzodiazepine Derivative as Noncompetitive AMPA Receptor Antagonis,” Journal of Medicinal Chemistry, Vol. 49, No. 2, 2006, pp. 575-581. doi:10.1021/jm050552y
[7] Y. Wang, C. S. Konkoy, V. I. Ilyin, K. E. Vanover, R. B. Carter, E. Weber, J. F. Keana, R. M. Woodward and S. X. Cai, “Synthesis of 7,8-(Methylenedioxy)-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones as Novel and Potent Noncompetitive AMPA Receptor Antagonists,” Journal of Medicinal Chemistry, Vol. 41, No. 14, 1998, pp. 26212625. doi:10.1021/jm980168j
[8] G. Abrahám, S. Sólyom, E. Csuzdi, P. Berzsenyi , I. Ling, I. Tarnawa, T. Hámori, I. Pallagi, K. Horváth, F. Andrási, G. Kapus, L. G. J. Hársing, I. Király, M. Patthy and G. Horváth, “New Noncompetitive AMPA Antagonists,” Bioorganic & Medicinal Chemistry, Vol. 8, No. 8, 2000, pp. 2127-2143 doi:10.1016/S0968-0896(00)00133-4
[9] T. Hámore, S. Sólyom, P. Berzsenyi, F. Andrási and I. Tarnawa, “Structural Analogues of Some Highly active Non-Competitive AMPA Antagonists,” Bioorganic & Medicinal Chemistry Letters, Vol. 10, No. 9, 2000, pp. 899902. doi:10.1016/S0960-894X(00)00117-7
[10] S. Grasso, G. De Sarro, A. De Sarro, N. Micale, M. Zappalà, G. Puia, M. Baraldi and C. D. Micheli, “Synthesis and Anticonvulsant Activity of Novel and Potent 2,3Benzodiazepine AMPA/Kainate Receptor Antagonists,” Journal of Medicinal Chemistry, Vol. 42, 1999, pp. 44144421. doi:10.1021/jm991086d
[11] J. J. Luszczki, “Third-Generation Antiepileptic Drugs: Mechanisms of Action, Pharmacokinetics and Interactions,” Pharmacological Reports, Vol. 61, No. 2, 2009, pp. 197-216
[12] M. L. Barreca, R. Gitto, S. Quartarone, D. L. Luca, G. D. Sarro and A. Chimirri, “Pharmacophore Modeling as an Efficient Tool in the Discovery of Novel Noncompetitive,” Journal of Chemical Information and Modeling, Vol. 43, No. 2, 2003, pp. 651-655.doi:10.1021/ci025625q
[13] J. F. Howes and C. Bell, “Talampanel,” Neurotherapeutics, Vol. 4, No. 1, 2007, pp. 126-129. doi:10.1016/j.nurt.2006.11.001
[14] R. Gitto, R. Caruso, V. Orlando, S. Quartarone, M. L. Barreca, G. Ferreri, E. Russo, G. D. Sarro and A. Chimirri, “Synthesis and Anticonvulsant Properties of Tetrahydroisoquinoline Derivative,” Farmaco, Vol. 59, No. 1, 2004, pp. 7-12. doi:10.1016/j.farmac.2003.10.003
[15] R. Gitto, R. Caruso, B. Pagano, L. D. Luca, R. Citraro, E. Russo, G. D. Sarro and A. Chimirri, “Novel Potent Anticonvulsant Agent Containing a Tetrahydroisoquinoline Kkeleton,” Journal of Medicinal Chemistry, Vol. 49, No. 18, 2006, pp. 5618-5622. doi:10.1021/jm060411b
[16] R. Gitto, B. Pagano, R. Citrato, F. Scicchitano, G. D. Sarro and A. Chimirri, “Solution-Phase Parallel Synthesis and Evaluation of Anticonvulsant Activity of N-Substituted3,4-dihydroisoquinoline-2(1H)-carboxamides,” European Journal of Medicinal Chemistry, Vol. 44, No. 3, 2009, pp. 1349-1354. doi:10.1016/j.ejmech.2008.02.025
[17] L. De Luca, R. Gitto, M. L. Barreca, R. Caruso, S. Quartarone, R. Citraro, G. D. Sarro and A. Chimirri, “3D Pharmacophore Models for 1,2,3,4-Tetrahydroisoquinoline Derivatives Acting as Anticonvulsant Agents,” Archiv der Pharmazie Chemistry in Life Sciences, Vol. 339, No. 7, 2006, pp. 388-400.
[18] K. J. Bough and D. A. Engel, “Comparison of the Anticonvulsant Efficacies and Neuroroxic Effects of Valproic Acid, Phehytoin, and the Ketogenic Diet,” Epilepsia, Vol. 42, No. 10, 2001, pp. 1345-1353. doi:10.1046/j.1528-1157.2001.08901.x
[19] J. B. Monent, I. Jorquera, I. Mazzucchelli, A. Depaulis, E. Perucca, Y. Ben-Ari and A. Represa, “Fetal Exposure to GABA-Acting Antiepileptic Drugs Generates Hippocampal and Cortical Dyspkasias,” Epilepsia, Vol. 48, No. 4, 2007, pp. 684-693. doi:10.1111/j.1528-1167.2007.01056.x
[20] V. B. Brito, V. Folmer, G. O. Puntel, R. Fachinetto, J. C. Soares, G. Zeni, C. W. Nogueira and J. B. Rocha, “Diphenyl Diselenide and 2,3-Dimercaptopropanol Increase the PTZ-Induced Chemical Seizure and Mortality in Mice,” Brain Research Bulletin, Vol. 68, No. 6, 2006, pp. 414418.
[21] A. Ilhan, M. A. Aladag, A. Kocer, A. Boluk, A. Gurel and F. Armutcu, “Erdosteine Ameliorates PTZ-Induced Oxidative Stress in Mice Seizure Model,” Brain Research Bulletin, Vol. 30, No. 6, 2005, pp. 495-499. doi:10.1016/j.brainresbull.2005.02.027
[22] N. B. Agarwal, S. Jain, D. Nagpal, N. K. Agarwal, P. K. Mediratta, K. K. Sharma, “Liposomal Formulation of Curcumin Attenuates Seizures in Different Experimental Models of Epilepsy in Mice,” Fundamental & Clinical Pharmacology, 2011. doi:10.1111/j.1472-8206.2011.01002.x
[23] A. Zandieh, F. Maleki, A. Hajimirzabeigi, B. Zandieh, O. Khalilzadeh and A. R. Dehpour, “Anticonvulsant Effect of Celecoxib on Pentylenetetrazole-Induced Convulsion: Modulation by NO Pathway,” Acta Neurobiologiae Experimentalis, Vol. 70, No. 4, 2010, pp. 390-397.

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