title: Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide.
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-GABAA 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 (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABAA 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.
authors.affiliation: Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, 15500 México City, DF, Mexico.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Garrido-Acosta
authors.affiliation: Laboratorio de Quimioterapia Experimental, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11350 México City, DF, Mexico.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Meza-Toledo
authors.affiliation: Laboratorio de Farmacología Molecular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 México City, DF, Mexico.
authors.forename: Liliana
authors.initials: L
authors.lastname: Anguiano-Robledo
authors.affiliation: Departamento de Fisiología, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 México City, DF, Mexico.
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Soriano-Ursúa
authors.affiliation: Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 México City, DF, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.affiliation: Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran 19419, Iran.
authors.forename: Asghar
authors.initials: A
authors.lastname: Davood
authors.affiliation: Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11350 México City, DF, Mexico.
authors.forename: Germán
authors.initials: G
authors.lastname: Chamorro-Cevallos
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D006843:Hydrocarbons, Chlorinated / Q000009:adverse effects / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000378:metabolism; D010666:Phenylpropionates / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D006843:Hydrocarbons, Chlorinated; D006845:Hydrocarbons, Fluorinated; D062551:NAV1.2 Voltage-Gated Sodium Channel; D010666:Phenylpropionates; D011963:Receptors, GABA-A; C067697:beta-hydroxy-beta-ethyl-phenylpropionamide