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BioMed Research International
Volume 2016, Article ID 3978010, 10 pages
http://dx.doi.org/10.1155/2016/3978010
Research Article

Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide

1Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, 15500 México City, DF, Mexico
2Laboratorio de Quimioterapia Experimental, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11350 México City, DF, Mexico
3Laboratorio de Farmacología Molecular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 México City, DF, Mexico
4Departamento de Fisiología, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 México City, DF, Mexico
5Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 México City, DF, Mexico
6Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran 19419, Iran
7Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11350 México City, DF, Mexico

Received 19 September 2015; Revised 21 January 2016; Accepted 26 January 2016

Academic Editor: Rituraj Purohit

Copyright © 2016 Osvaldo Garrido-Acosta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets— receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor.