Structure-activity relationship of phenytoinergic antiepileptic drugs related to ameltolide

Philip, Ashok E.;Poupaert, Jacques;Cheve, Gwenael;Muccioli, Giulio;McCurdy, Christopher R.;et.al.
(2007) Medicinal Chemistry Research : an international journal for rapid communications on design and mechanisms of action of biologically active agents — Vol. 16, n° 3, p. 130-135 (2007)

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Authors
  • Philip, Ashok E.
    Author
  • Poupaert, JacquesUCLouvain
    Author
  • Cheve, Gwenael
    Author
  • Muccioli, Giulioorcid-logoUCLouvain
    Author
  • Lambert, Didierorcid-logoUCLouvain
    Author
  • McCurdy, Christopher R.
    Author
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Abstract
Ameltolide shares with phenytoin and carbamazepine a common mode of action involving interaction with central voltage-dependent sodium channels. Ameltolide and structurally related benzanilides were subjected to molecular modeling studies using both molecular mechanics (MM2, Amber96, and OPLS) and semiempirical quantum mechanics (AM], PM3, and PM3 Cosmo) to resolve a paradox: while compounds with a phenytoin-like pharmacological profile possess a CO-NH moiety in a cis-configuration, ameltolide was found via X-ray crystallography to exist in the trans-configuration. Results obtained both by molecular mechanics and semiempirical methods indicate that for ameltolide, the cis and trans forms have similar energy content. Additional ab initio calculations performed at 63 31G** gave a Delta E (Z - E) on the order of 3 kcal/mol. In view of this small energy difference between the cis and trans forms, it is conceivable that these benzanilides bind to their biological target in their cis configuration, therefore assuming a common structure-activity relationship with classical antiepileptic agents.
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Philip, A. E., Poupaert, J., Cheve, G., Muccioli, G., Lambert, D., & McCurdy, C. R. (2007). Structure-activity relationship of phenytoinergic antiepileptic drugs related to ameltolide. Medicinal Chemistry Research : an international journal for rapid communications on design and mechanisms of action of biologically active agents, 16(3), 130-135. https://doi.org/10.1007/s00044-007-9016-9 (Original work published 2007)