4-Substituted carbamazepine derivatives: Conformational analysis and sodium channel-blocking properties

Bioorg Med Chem. 2018 May 15;26(9):2508-2513. doi: 10.1016/j.bmc.2018.04.013. Epub 2018 Apr 5.

Abstract

The physicochemical properties of 4-substituted carbamazepine derivatives were investigated. It was elucidated that the 4-substitution is not effective in reducing the rotations (E/Z) about the N-C1' axes around the outer carbamoyl moiety. However, the atropisomers were isolated with high stereochemical stability, meaning that the 4-substitution reduced the butterfly motion of the tricyclic ring system efficiently. The Cl/CH3-substituted carbamazepine derivatives showed greater inhibitory effects on hNav1.2 channel currents compared with carbamazepine, although no difference in the activity between enantiomers was observed.

Keywords: Atropisomerism; Carbamazepine; Sodium channel; Urea.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Carbamazepine / analogs & derivatives*
  • Carbamazepine / chemical synthesis
  • Carbamazepine / chemistry
  • Carbamazepine / pharmacology*
  • Cricetulus
  • Humans
  • Molecular Conformation
  • NAV1.2 Voltage-Gated Sodium Channel / metabolism*
  • Sodium Channel Blockers / chemical synthesis
  • Sodium Channel Blockers / chemistry
  • Sodium Channel Blockers / pharmacology*
  • Stereoisomerism
  • Temperature
  • Thermodynamics

Substances

  • NAV1.2 Voltage-Gated Sodium Channel
  • Sodium Channel Blockers
  • Carbamazepine