Theoretical study of mexiletine and its interaction with cationic and anionic receptor sites

Farmaco. 1999 Oct 30;54(10):653-9. doi: 10.1016/s0014-827x(99)00074-9.

Abstract

Theoretical methods are applied to study the antiarrhythmic (AA) mexiletine (1-(2,6-dimethylphenoxy)-2-aminopropane). The AM1 method is used to construct a three-centre binding model for this drug. This model consists of an amine nitrogen atom that is protonated to a higher degree at physiological pH, flat hydrophobic regions of aromatic rings and additional functional groups with lone electron pairs of oxygen. Based on these ideas, a model for the binding of mexiletine at the transmembrane protein was constructed. An ab initio SCF method was used to study the two-component mexiletine-receptor binding site composed of acetate (Glu-, Asp-) and protonated methylamine (Lys+, Arg+). The binding of mexiletine to the receptor may be understood by considering a two-step process of recognition and binding of AA to its receptor. Within this model the mexiletine cation is recognised in the first step and bonded to the negatively-charged part of the receptor. In a subsequent step, the interaction between the amide oxygen and cationic amine group of the membrane protein may follow.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Arrhythmia Agents / chemistry*
  • Binding Sites
  • Mexiletine / chemistry*
  • Mexiletine / metabolism
  • Models, Molecular
  • Receptors, Drug / chemistry*
  • Receptors, Drug / metabolism
  • Stereoisomerism

Substances

  • Anti-Arrhythmia Agents
  • Receptors, Drug
  • Mexiletine