Classification of drugs based on properties of sodium channel inhibition: a comparative automated patch-clamp study.
PLoS One
; 5(12): e15568, 2010 Dec 20.
Article
in En
| MEDLINE
| ID: mdl-21187965
ABSTRACT
BACKGROUND:
There is only one established drug binding site on sodium channels. However, drug binding of sodium channels shows extreme promiscuity â¼25% of investigated drugs have been found to potently inhibit sodium channels. The structural diversity of these molecules suggests that they may not share the binding site, and/or the mode of action. Our goal was to attempt classification of sodium channel inhibitors by measuring multiple properties of inhibition in electrophysiology experiments. We also aimed to investigate if different properties of inhibition correlate with specific chemical properties of the compounds. METHODOLOGY/PRINCIPALFINDINGS:
A comparative electrophysiological study of 35 compounds, including classic sodium channel inhibitors (anticonvulsants, antiarrhythmics and local anesthetics), as well as antidepressants, antipsychotics and neuroprotective agents, was carried out using rNav1.2 expressing HEK-293 cells and the QPatch automatic patch-clamp instrument. In the multi-dimensional space defined by the eight properties of inhibition (resting and inactivated affinity, potency, reversibility, time constants of onset and offset, use-dependence and state-dependence), at least three distinct types of inhibition could be identified; these probably reflect distinct modes of action. The compounds were clustered similarly in the multi-dimensional space defined by relevant chemical properties, including measures of lipophilicity, aromaticity, molecular size, polarity and electric charge. Drugs of the same therapeutic indication typically belonged to the same type. We identified chemical properties, which were important in determining specific properties of inhibition. State-dependence correlated with lipophilicity, the ratio of the neutral form of molecules, and aromaticity We noticed that the highly state dependent inhibitors had at least two aromatic rings, logP>4.0, and pKa<8.0. CONCLUSIONS/SIGNIFICANCE:
The correlations of inhibition properties both with chemical properties and therapeutic profiles would not have been evident through the sole determination of IC(50); therefore, recording multiple properties of inhibition may allow improved prediction of therapeutic usefulness.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sodium Channel Blockers
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
PLoS One
Journal subject:
CIENCIA
/
MEDICINA
Year:
2010
Document type:
Article
Affiliation country:
Hungary
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA