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Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide
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),...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Hindawi Publishing Corporation
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783531/ https://www.ncbi.nlm.nih.gov/pubmed/27006945 http://dx.doi.org/10.1155/2016/3978010 |
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author | Garrido-Acosta, Osvaldo Meza-Toledo, Sergio E. Anguiano-Robledo, Liliana Soriano-Ursúa, Marvin A. Correa-Basurto, José Davood, Asghar Chamorro-Cevallos, Germán |
author_facet | Garrido-Acosta, Osvaldo Meza-Toledo, Sergio E. Anguiano-Robledo, Liliana Soriano-Ursúa, Marvin A. Correa-Basurto, José Davood, Asghar Chamorro-Cevallos, Germán |
author_sort | Garrido-Acosta, Osvaldo |
collection | PubMed |
description | 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—GABA(A) receptors and the sodium channel Nav1.2. The median effective doses (ED(50)) 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 ED(50) against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABA(A) 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. |
format | Online Article Text |
id | pubmed-4783531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-47835312016-03-22 Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide Garrido-Acosta, Osvaldo Meza-Toledo, Sergio E. Anguiano-Robledo, Liliana Soriano-Ursúa, Marvin A. Correa-Basurto, José Davood, Asghar Chamorro-Cevallos, Germán Biomed Res Int Research Article 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—GABA(A) receptors and the sodium channel Nav1.2. The median effective doses (ED(50)) 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 ED(50) against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABA(A) 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. Hindawi Publishing Corporation 2016 2016-02-24 /pmc/articles/PMC4783531/ /pubmed/27006945 http://dx.doi.org/10.1155/2016/3978010 Text en Copyright © 2016 Osvaldo Garrido-Acosta et al. https://creativecommons.org/licenses/by/4.0/ 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. |
spellingShingle | Research Article Garrido-Acosta, Osvaldo Meza-Toledo, Sergio E. Anguiano-Robledo, Liliana Soriano-Ursúa, Marvin A. Correa-Basurto, José Davood, Asghar Chamorro-Cevallos, Germán Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide |
title | Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide |
title_full | Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide |
title_fullStr | Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide |
title_full_unstemmed | Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide |
title_short | Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide |
title_sort | anticonvulsant and toxicological evaluation of parafluorinated/chlorinated derivatives of 3-hydroxy-3-ethyl-3-phenylpropionamide |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783531/ https://www.ncbi.nlm.nih.gov/pubmed/27006945 http://dx.doi.org/10.1155/2016/3978010 |
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