Psychiatric drugs and classic sodium channel inhibitors differ in their mechanisms of action on rNav1.2 channels: an automated patch-clamp study
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1
Institute of Experimental Medicine, Hungarian Academy of Sciences, Hungary
All clinically used sodium channel inhibitors (SCIs) cause voltage- and use-dependent inhibition. However, biophysical properties of inhibition can differ widely even between use-dependent SCIs which seem to act similarly. Regarding the therapeutical potential of the drugs, it has been proposed that the mechanism of inhibition can be more important than potency or isoform-selectivity. In this study we tested, if biophysical properties of the inhibition correlate with therapeutic profile. We investigated 25 use-dependent SCIs of different chemical structure and therapeutic indication, including local anesthetics (bupivacaine, lidocaine), anticonvulsants (carbamazepine, phenytoine, topiramate, zonisamide, crobenetine, CO 102862), antiarrhytmics (mexiletine, flecainide, procainamide), antidepressants (amitriptyline, desipramine, imipramine, mianserin, fluoxetine, sertraline, paroxetine), antipsychotics (haloperidol, chlorpromazine, clozapine), antispastic agents (tolperisone, silperisone), and drugs of other indications (ritanserine, ambroxol). SCIs were tested on rNav1.2 expressing HEK 293 cells, using the QPatch HT system (Sophion Bioscience, Denmark). We studied the development of inactivation in parallel with association, the recovery from inactivation in parallel with dissociation, the pH dependence of inhibition. We observed that properties of inhibition correlate with therapeutic profile much more than with chemical structure; which suggests that biophysical property-sensitive screening of SCI drugs could be a useful strategy in drug development.
Conference:
12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009.
Presentation Type:
Poster Presentation
Topic:
Developmental neurobiology and subcortical functions
Citation:
Lenkey
N,
Mike
Á,
Károly
R and
Vizi
SE
(2009). Psychiatric drugs and classic sodium channel inhibitors differ in their mechanisms of action on rNav1.2 channels: an automated patch-clamp study.
Front. Syst. Neurosci.
Conference Abstract:
12th Meeting of the Hungarian Neuroscience Society.
doi: 10.3389/conf.neuro.01.2009.04.063
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Received:
02 Mar 2009;
Published Online:
02 Mar 2009.
*
Correspondence:
Nóra Lenkey, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary, lenkeyn@koki.hu