Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Neuropharmacological Screening of Chiral and Non-chiral Phthalimide- Containing Compounds in Mice: in vivo and in silico Experiments

Author(s): Carolina Campos-Rodríguez, José G. Trujillo-Ferrara*, Ameyali Alvarez-Guerra, Irán M. Cumbres Vargas, Roberto I. Cuevas-Hernández, Erik Andrade-Jorge, Sergio Zamudio and Eduardo R.-S. Juan*

Volume 15, Issue 1, 2019

Page: [102 - 118] Pages: 17

DOI: 10.2174/1573406414666180525082038

Price: $65

Abstract

Background: Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties.

Objective: Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested.

Method: Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg).

Results: The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate.

Conclusion: The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.

Keywords: Phthalimide moiety, sedative, anticonvulsant, mice, thalidomide, glutamate, chirality.

Graphical Abstract
[1]
Hashimoto, Y. Structural development of biological response modifiers based on thalidomide. Bioorgan. Med. Chem., 2002, 10, 461-479.
[2]
Meltchert, M.; List, A. The thalidomide saga. Int. J. Biochem. Cell B., 2007, 39, 1489-1499.
[3]
Franks, M.E.; Macpherson, G.R.; Figg, W.D. Thalidomide. Lancet, 2004, 363, 1802-1811.
[4]
Casal, J.J.; Bollini, M.; Lombardo, M.L.; Bruno, A.M. Thalidomide analogues: Tumor necrosis factor-alpha inhibitors and their evaluation as anti-inflammatory agents. Eur. J. Pharm. Sci., 2016, 83, 114-119.
[5]
Palencia, G.; Núñez-Medrano, J.; Ortiz-Plata, A.; Jiménez-Farfán, D.; Sotelos, J.; Sánchez, A.; Trejo-Solís, C. Anti-apoptotic, anti-oxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/reperfusion injury in rats. J. Neurol. Sci., 2015, 351, 78-87.
[6]
Palencia, G.; Calderon, A.; Sotelo, J. Thalidomide inhibits pentylenetetrazole-induced seizures. J. Neurol. Sci., 2007, 258, 128-131.
[7]
Payandemehr, B.; Rahimian, R.; Gooshe, M.; Bahremand, A.; Gholizadeh, R.; Berijani, S.; Ahmadi-Dastegerdi, M.; Aminizade, M.; Sarreshte-Dari, A.; Dianati, V.; Amanlou, M.; Dehpour, A.R. Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced tonic seizures in mice. Epilepsy Behav., 2014, 34, 99-104.
[8]
Marjanovic, B.D.; Stojanov, L.M.; Zdravkovic, D.S.; Kravljanac, R.M.; Djordjevic, M.S. Rasmussen syndrome and long term response to thalidomide. Pediatr. Neurol., 2003, 29, 151-156.
[9]
Palencia, G.; Martinez-Juarez, I.E.; Calderon, A.; Artigas, C.; Sotelo, J. Thalidomide for treatment of refractory epilepsy. Epilepsy Res., 2010, 92, 253-257.
[10]
Boireau, A.; Bordier, F.; Dubédat, P.; Pény, C.; Impérato, A. Thalidomide reduces MPTP induced decrease in striatal dopamine levels in mice. Neurosci. Lett., 1997, 234, 123-126.
[11]
Hyakkoku, K.; Nakajima, Y.; Izuta, H.; Shimazawa, M. Thalidomide protects against ischemic neuronal damage induced by focal cerebral ischemia in mice. Neuroscience, 2009, 159, 760-769.
[12]
Palencia, G.; García, E.; Osorio-Rico, L.; Trejo-Solís, C.; Escamilla-Ramírez, A.; Sotelo, J. Neuroprotective effect of thalidomide on MPTP-induced toxicity. Neurotoxicology, 2015, 47, 82-87.
[13]
Ribeiro, R.A.; Vale, M.L.; Ferreira, S.H.; Cunha, F.Q. Analgesic effect of thalidomide on inflammatory pain. Eur. J. Pharmacol., 2000, 391, 97-103.
[14]
Matthews, S.J.; McCoy, C. Thalidomide: a review of approved and investigational uses. Clin. Ther., 2003, 23(2), 342-395.
[15]
Leite, A.C.L.; Barbosa, F.F.; Cardoso, M.V.O.; Moreira, D.R.M.; Coêhlo, L.C.D.; da Silva, E.B.; Filho, G.B.O.; de Souza, V.M.O.; Pereira, V.R.A.; Reis, L. de C.; Ferreira, P.M.P.; Pessoa, C.; Wanderley, A.G.; Mota, F.V.B.; Da Silva, T.G. Phthaloyl amino acids as anti-inflammatory and immunomodulatory prototypes. Med. Chem. Res., 2014, 23, 1701-1708.
[16]
Godin, A.M.; Araújo, D.P.; Menezes, R.R.; Brito, A.M.S.; Melo, I.S.F.; Coura, G.M.E.; Soares, D.G.; Bastos, L.F.S.; Amaral, F.A.; Ribeiro, L.S.; Boff, D.; Santos, J.R.A.; Santos, D.A.; Teixeira, M.M.; de Fátima, A.; Machado, R.R.; Coelho, M.M. Activities of 2 phthalimidethanol and 2 phthalimidethyl nitrate, phthalimide analogs devoid of the glutarimide moiety, in experimental models of inflammatory pain and edema. Pharmacol. Biochem. Behav., 2014, 122, 291-298.
[17]
Zeng, Q.; Liu, Z.; Li, B.; Wang, F. Mild and effective N-phthaloylation of amino acids. Amino Acids, 2014, 27, 183-186.
[18]
Homsi, A.; Kasideh, A. synthesis of some N-phthalimide amino acids derivatives and evaluation their biological activity. Int. J. Chemtech Res., 2015, 8(4), 1817-1825.
[19]
Singh, G.; Saroa, A.; Girdhar, S.; Rani, S.; Sahoo, S.; Choquesillo-Lazarte, D. Synthesis, characterization, electronic absorption and antimicrobial studies of N (silatranylpropyl)phthalimide derived from phthalic anhydride. Inorg. Chim. A. Lett., 2015, 427, 232-239.
[20]
Ahmed, H.E.A.; Abdel-Salam, H.A.; Shaker, M.A. Synthesis, characterization, molecular modeling, and potential antimicrobial and anticancer activities of novel 2-aminoisoindoline-1,3-dione derivatives. Bioorg. Chem., 2016, 66, 1-11.
[21]
Kushwaha, N.; Kaushik, D. Recent advances and future prospects of phthalimide derivatives. JAPS, 2016, 6(03), 159-171.
[22]
Alibadi, A.; Gholamine, B.; Karimi, T. Synthesis and antiseizure evaluation of isoindoline-1,3-dione derivatives in mice. Med. Chem. Res., 2014, 23, 2736-2743.
[23]
Antunes, R.; Batista, H.; Srivastava, R.M.; Thomas, G.; Araujo, C.C. New phthalimide derivatives with potent analgesic activity: II. Bioorg. Med. Chem. Lett., 1998, 8, 3071-3076.
[24]
Kumar, C.S.C.; Loh, W-S.; Chandraju, S.; Win, Y-F.; Tan, W.K.; Quah, C.K.; Fun, H-K. Synthesis, structural and antioxidant studies of some novel N-ethyl phthalimide esters. PLoS One, 2015, 10(3), e0119440.
[25]
Vamecq, J.; Bac, P.; Herrenknecht, C.; Maurois, P.; Delcourt, P.; Stables, J.P. Synthesis and anticonvulsant and neurotoxic properties of substituted N-phenyl derivatives of the phthalimide pharmacophore. J. Med. Chem., 2000, 43(7), 1311-1319.
[26]
Faghihi, K.; Absalar, M.; Hajibeygi, M. Synthesis and characterization of new optically active polyamides containing 2-(4-nitro-1,3-dioxoisoindolin-2-yl)succinic acid and aromatic diamines via direct polycondensation. Turk. J. Chem., 2010, 34(1), 81-90.
[27]
Flores-Soto, M.E.; Chaparro-Huerta, V.; Escoto-Delgadillo, M.; Vazquez-Valls, E.; Gonzalez-Castañeda, R.E.; Beas-Zarate, C. Estructura y función de las subunidades del receptor a glutamato tipo NMDA. Neurologia, 2012, 27, 301-310.
[28]
Apweiler, R.; Bairoch, A.; Wu, C.H.; Barker, W.C.; Boeckmann, B.; Ferro, S.; Gasteiger, E.; Huang, H.; Lopez, R.; Magrane, M.; Martin, M.J.; Natale, D.A.; O’Donovan, C.; Redaschi, N.; Yeh, L.S. UniProt: The Universal Protein knowledgebase. Nucleic Acids Res., 2014, 32, D115-D119.
[29]
Karakas, E.; Furukawa, H. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science, 2014, 344(6187), 992-997.
[30]
Eswar, N.; Webb, B. Marti-Renom, Ma, A.; Madhusudhan, M.S.; Eramian, D.; Shen, M.Y.; Pieper, U.; Sali, A. Comparative Protein Structure Modeling Using Modeller In: Current Protocols in Bioinformatics; Bateman, A.; Draghici, S.; Khuran, E.; Orchard, S.; Pearson, W.R., Eds.; John Wiley & Sons, Inc., New Jersey, 2006. 5.6.1-5.6.30.
[31]
Lovell, S.C.; Davis, I.W.; Arendall, W.B.; De Bakker, P.I.W.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Cα geometry: φ,ψ and Cβ deviation. Proteins, 2015, 50(3), 437-450.
[32]
Tautermann, C.S. GPCR Homology Model Generation for Lead Optimization. Methods Mol. Biol., 2018, 1705, 115-131.
[33]
Wu, H.; Wang, C.; Gregory, K.J.; Han, G.W.; Cho, H.P.; Xia, Y.; Niswender, C.M.; Katritch, V.; Meiler, J.; Cherezov, V.; Conn, P.J.; Stevens, R.C. Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator. Science, 2014, 344(6179), 58-64.
[34]
Dassault Systèmes, B.I.O.V.I.A. Discovery Studio Modeling Environment, Release 2017; San Diego: Dassault Systèmes, 2016.
[35]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A.; Bloino, J.; Janesk, R.; Gomperts, B.; Mennucci, B.; Hratchian, H.P.; Ortiz, J.V.; Izmaylov, A.F.; Sonnenberg, J.L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V.G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Vreven, T.; Throssell, K.; Montgomery, Jr , J.A.; Peralta, J.E.; Olgliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghvachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Romasi, J.; Cossi, M.; Millam, J.M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, W.; Martin, R.L.; Morokuma, K.; Farkas, O.; Foresman, J.B.; Fox, D.J. Gaussian 09, Revision A.02; Gaussian, Inc.: Wallingford, CT, 2016.
[36]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[37]
Forli, S.; Huey, R.; Pique, M.E.; Sanner, M.F.; Goodsell, D.S.; Olson, A.J. Computational protein ligand docking and virtual drug screening with the AutoDock suite. Nat. Protoc., 2016, 11, 905-919.
[38]
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function. J. Comput. Chem., 1998, 19(14), 1639-1662.
[39]
Ryu, J.K.; McLarnon, J.G. Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor- α in an animal model of inflamed Alzheimer’ s disease brain. Neurobiol. Dis., 2008, 29, 254-266.
[40]
Prut, L.; Belzung, C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur. J. Pharmacol., 2003, 463, 3-33.
[41]
Lopez-Martinez, M.; Salgado-Zamora, H.; Ramirez-San Juan, E.; Zamudio, S.; Picazo, O.; Campos, M.E.; Naranjo-Rodriguez, E.B. Anti-anxiety and sedative profile evaluation of imidazo[1,2-a]pyridine derivatives. Drug Develop. Res., 2010, 71(6), 371-381.
[42]
Blumstein, D.T.; Daniel, J.C.; Evans, C.S. JWatcher v.1.0. http://www.jwatcher.ucla.edu/ (Accessed June 21, 2017)
[43]
Walf, A.A.; Frye, C.A. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat. Protoc., 2007, 2(2), 322-328.
[44]
Sorregotti, T.; Mendes-Gomes, J.; Rico, J.L.; Rodgers, R.J.; Nunes-de-Souza, R.L. Ethopharmacological analysis of the open elevated plus-maze in mice. Behav. Brain Res., 2013, 246, 76-85.
[45]
Vinitha, E.; Singh, H.J.C.; Kakalij, R.M.; Kshirsagar, R.P.; Kumar, B.H.; Diwan, P.V. Neuroprotective effect of Prunus avium on streptozotocin induced neurotoxicity in mice. Biomed. Prev. Nutr., 2014, 4(4), 519-525.
[46]
Thakur, A.; Sahai, A.; Thakur, J. Experimental re-evaluation of flunarizine as add-on antiepileptic therapy. J. Pharm. Bioallied Sci., 2011, 3(2), 253-258.
[47]
Yamaguchi, S.; Rogawski, M.A. Effects of anticonvulsant drugs on 4-aminopyridine induced seizures in mice. Epilepsy Res., 1992, 11, 9-16.
[48]
Sancheti, J.; Shaikh, M.F.; Chaudhari, R.; Somani, G.; Patil, S.; Jain, P.; Sathaye, S. Characterization of anticonvulsant and antiepileptogenic potential of thymol in various experimental models. N-S Arch. Pharmacol., 2014, 387, 59-66.
[49]
Bronowska, A.K. Thermodynamics of ligand-protein interactions: Implications for molecular design In: Thermodynamics – Ineraction studies – solids, liquids and gases; Moreno-Pirajan J.C., Ed.; InTech, 2011. Available from: https://www.intechopen.com/books/ thermodynamics-interaction-studies-solids-liquids-and-gases/ther-modynamics-of-ligand-protein-interactions-implications-for-mole-cular-design
[50]
Du, X.; Li, Y.; Xia, Y.L.; Ai, S.M.; Liang, J.; Sang, P.; Ji, X.L.; Liu, S.Q. Insights into protein-ligand interactions: mechanisms, models, and methods. Int. J. Mol. Sci., 2016, 17(144), 1-34.
[51]
Lorke, D. A new approach to practical acute toxicity testing. Arch. Toxicol., 1983, 54(4), 275-287.
[52]
Danysz, W.; Essmann, U.; Bresink, I.; Wilke, R. Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol. Biochem. Behav., 1994, 48(1), 111-118.
[53]
Kim, J-H.; Vezina, P. Blockade of glutamate reuptake in the rat nucleus accumbens increases locomotor activity. Brain Res., 1999, 819, 165-169.
[54]
Langen, M.; Kas, M.J.H.; Staal, W.C.; van Engeland, H.; Durston, S. The neurobiology of repetitive behavior: Of mice…. Neurosci. Behav. R., 2011, 35, 345-355.
[55]
Castañé, A.; Santana, N.; Artigas, F. PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments. Psychopharmacol., 2015, 232, 4085-4097.
[56]
Niswender, C.M.; Conn, P.J. Metabotropic glutamate receptors: physiology, pharmacology and disease. Annu. Rev. Pharmacol. Toxicol., 2010, 50, 295-322.
[57]
Fragoso-Veloz, J.; Tapia, R. NMDA receptor antagonists protect against seizures and wet-dog shakes induced by 4-aminopyridine. Eur. J. Pharmacol., 1992, 221, 275-280.
[58]
Vamecq, J. Van derpiorten, K.; Poupaert, J.H.; Balzarin, J.; De Clercq, E.; Stables, J.P. Anticonvulsant phenytoinergic pharmacophores and anti-HIV activity-preliminary- evidence for the dual requirement of the 4-aminophthalimide plataform and the N-(1-adamantyl) substitution for antiviral properties. Life Sci., 1998, 63(19), 267-274.
[59]
Morales-Villagrán, A.; Ureña-Guerero, M.E.; Tapia, R. Protection by NMDA receptor antagonists against seizures induced by intracerebral administration of 4-aminopyridine. Eur. J. Pharmacol., 1996, 305, 87-93.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy