In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

Abstract

Background: Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications. Methods: Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice. Results: Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED 50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tertButylcyclo-hexanecarboxylic acid showed significant activity with ED 50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. Conclusion: Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.

Anti-Seizure Activity of 1-Adamantane Carboxylic Acid in Common Experimental Seizure Models: Role of Benzodiazepine-GABAA Receptors

“…AdCA also showed sedative effect; the anti-seizure effect of AdCA appeared at the sedative doses. This finding is in line with our previous study in which the non-sedative doses of AdCA did not show anticonvulsant activity in PTZ and MES models [2] . Results of our study showed that the margin between sedative and anticonvulsant doses of AdCA was narrow in the PTZ model as PI value of 0.87 was obtained for AdCA.…”

“…Using bioinformatics tools and pharmacophore drug design, we have previously introduced several compounds with potential anticonvulsant activity [2] . Though all candidate molecules had adequate safety, a few compounds were effective in experimental seizure models [2] . One of the candidate molecules was AdCA (Fig.…”

“…administration to mice [3] . We examined the effect of non-sedative doses of AdCA but did not find any anticonvulsant activity [2] . However, in the report of Fridman et al [3] , it has not mentioned whether any sedative effect is detected at the anticonvulsant doses.…”

Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) in Mice

“…Other methods suggest changing a chemical structure of known AEDs or phenotypic screening of compounds with unknown mechanisms [7,8]. In silico methods are the useful tools, which help to predict biological activity and structure of designed compounds [11]. Moreover, these tools are able to notice phenotypic and genotypic differences between AEDs in polytherapy [12].…”