Sodium channel inhibitors have multiple mechanisms of action - a comparative electrophysiological study of 43 drugs
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1
Hungarian Academy of Sciences, Institute of Experimental Medicine, Hungary
Drugs of many different therapeutic indications have sodium channel inhibitor (SCI) property, e.g. many anticonvulsants, antiarrhytmics, local anesthetics, antipsychotics, and neuroprotective agents. Interestingly, antidepressants were found to be the therapeutic group with the highest incidence of SCI activity. Our aim was to elucidate if SCI property is a general attribute of antidepressants and if so, whether they possess a special mechanism of action. We also intended to explore which chemical properties of drugs explain the diversity in their mode of action. A comparative electrophysiological study of 16 antidepressants, and 27 other SCI compounds was performed using rNav1.2 expressing HEK 293 cells and the QPatch automatic patch-clamp instrument. Calculation of chemical descriptors were performed using ChemAxon softwares.
SCIs were found to be heterogeneous regarding their properties of inhibition, which probably reflects distinct modes of action. All antidepressants except the two monoamin oxidase inhibitors were potent SCIs. A subset of antidepressants (tricyclic compounds and selective serotonin reuptake inhibitors) inhibited sodium channels in a special way (with high affinity, slow kinetics and poor reversibility), which was clearly different from the inhibition caused by classic SCIs (low affinity, fast kinetics, and good reversibility). Other types of antidepressants were heterogenous regarding the mode of inhibition. Significant correlation was found between properties of inhibition, chemical properties, and therapeutic profile of drugs, most notably partition coefficient (logP) showed a high correlation with potency of SCIs.
Recording multiple properties of inhibition revealed correlations both with chemical properties and therapeutic profile that would have been hidden if only the IC50 had been determined; therefore this method may allow improved prediction of therapeutic usefulness.
Conference:
IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010.
Presentation Type:
Poster Presentation
Topic:
Cellular neuroscience
Citation:
Lenkey
N,
Mike
A,
Karoly
R and
Vizi
SE
(2010). Sodium channel inhibitors have multiple mechanisms of action - a comparative electrophysiological study of 43 drugs.
Front. Neurosci.
Conference Abstract:
IBRO International Workshop 2010.
doi: 10.3389/conf.fnins.2010.10.00077
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Received:
21 Apr 2010;
Published Online:
21 Apr 2010.
*
Correspondence:
Nora Lenkey, Hungarian Academy of Sciences, Institute of Experimental Medicine, Budapest, Hungary, lenkeyn@koki.hu