Chemical properties of sodium channel inhibitors which determine affinity to resting and inactivated states
-
1
Institute of Experimental Medicine, Department of Pharmacology, Hungary
Affinity of inhibitor compounds to hyperpolarized and depolarized conformations of sodium channels (commonly termed resting and inactivated affinities: Kr and Ki) were investigated: Their correlations with chemical descriptors of inhibitors were studied, in order to deduce the nature of chemical interactions involved in binding to both conformations. Two separate approaches were used: (1) We performed a literature search, calculated Kr and Ki values, and created a database of altogether 204 Kr-Ki pairs obtained from 73 publications. (2) We carried out a comparative electrophysiological study of 35 drugs using rNav1.2 expressing HEK 293 cells and the QPatch automatic patch-clamp instrument. We observed that lipophilicity (quantified by the logarithm of the calculated water-octanol partition coefficient, logP) is important in determining both Kr and Ki, but had a greater effect on Ki. Distribution coefficients (logD) discriminated better between Kr and Ki than partition coefficients (logP). The ratio of positively charged/neutral forms (quantified by the acidic dissociation constant, pKa) was a significant determinant of resting affinity: predominantly charged compounds tended to be more potent against resting channels, while neutral compounds tended to be more state-dependent. Aromaticity was more important for inactivated state affinity.
Keywords:
Neurophysiology,
Neuroscience
Conference:
13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011.
Presentation Type:
Abstract
Topic:
Neurophysiology
Citation:
Lenkey
N,
Epresi
N,
Sas
B,
Vizi
ES and
Mike
A
(2011). Chemical properties of sodium channel inhibitors which determine affinity to resting and inactivated states.
Front. Neurosci.
Conference Abstract:
13th Conference of the Hungarian Neuroscience Society (MITT).
doi: 10.3389/conf.fnins.2011.84.00169
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Received:
03 Mar 2011;
Published Online:
23 Mar 2011.
*
Correspondence:
Dr. A. Mike, Institute of Experimental Medicine, Department of Pharmacology, Budapest, Hungary, arpadmike1@gmail.com