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. 2016:2016:3978010.
doi: 10.1155/2016/3978010. Epub 2016 Feb 24.

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

Osvaldo Garrido-Acosta  1 , Sergio E Meza-Toledo  2 , Liliana Anguiano-Robledo  3 , Marvin A Soriano-Ursúa  4 , José Correa-Basurto  5 , Asghar Davood  6 , Germán Chamorro-Cevallos  7
Affiliations

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

Osvaldo Garrido-Acosta et al. Biomed Res Int. 2016.

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.

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Figures

Figure 1
Figure 1
The effect of the tested compounds on two seizure models. (a) The effect of administering the ED50 against maximal electroshock seizures: HEPP = 129.6 mg/kg, F-HEPP = 87.1 mg/kg, Cl-HEPP = 62.0 mg/kg, sodium valproate = 261.2 mg/kg, and phenobarbital = 16.9 mg/kg; (b) the effect of administering the ED50 against pentylenetetrazole seizures: HEPP = 66.4 mg/kg, F-HEPP = 43.5 mg/kg, Cl-HEPP = 43.5 mg/kg, sodium valproate = 159.7 mg/kg, and phenobarbital = 12.9 mg/kg. n = 12. Black bar, mice with seizures; grey bar, mice without seizures; ISS, isotonic saline solution (NaCl 0.09%); PEG-400 (30%), polyethyilenglicol-400 at 30% with ISS. For the hypothesis test, the percentage of protection was 50% in order to determine the proportion response of the antiepileptic drugs. According to the Z-test, there was no statistically significant difference between mice protected against seizures with antiepileptic drugs and unprotected mice.
Scheme 1
Scheme 1
Chemical structure of compounds tested in this study. (a) 3(R)-3-Hydroxy-3-ethyl-3-phenylpropionamide, (R)-HEPP; (b) 3(R)-3-hydroxy, 3-ethyl, 3-(4′-chlorophenyl)propionamide, (R)-Cl-HEPP; (c) 3(R)-3-hydroxy, 3-ethyl, 3-(4′-fluorophenyl)propionamide, (R)-F-HEPP; (d) 3(S)-3-hydroxy-3-ethyl-3-phenylpropionamide, (S)-HEPP; (e) 3(S)-3-hydroxy, 3-ethyl, 3-(4′-chlorophenyl)propionamide, (S)-Cl-HEPP; (f) 3(S)-3-hydroxy, 3-ethyl, 3-(4′-fluorophenyl)propionamide, (S)-F-HEPP.
Figure 2
Figure 2
Effect on the rotarod test produced by the administration of different doses of HEPP, F-HEPP, Cl-HEPP, sodium valproate, and phenobarbital. n = 8. Black bar, selection test (180 s = 100%); grey bar, evaluation test (expressed as the median + standard error of the mean). The doses administered for each treatment were ED50 against PTZ < ED50 against MES < twice ED50 against MES. ISS, isotonic saline solution (NaCl 0.09%); PEG-400 (30%), polyethyilenglicol-400 at 30% with ISS. Kruskal-Wallis post hoc Dunn's, ∗statistically significant difference with respect to the selection test (p < 0.05).
Figure 3
Figure 3
Mode of binding of (R)-HEPP, (R)-Cl-HEPP, and (R)-F-HEPP at the benzodiazepine binding site of the GABAA receptor.
Figure 4
Figure 4
Mode of binding of phenytoin, (R)-HEPP, (R)-Cl-HEPP, and (R)-F-HEPP on the sodium channel Nav1.2.
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