Title:Identification of Novel NaV1.7 Antagonists Using High Throughput Screening Platforms
VOLUME: 15 ISSUE: 9
Author(s):Goran Klement, Olga Babich, Olof Larsson, Per-Eric Lund, Asa Malmberg, Lars Sandberg, Zara A. Sands and Michael Dabrowski
Affiliation:AstraZeneca R&D, CNSP iMed, B209, SE-15185 Sodertalje, Sweden.
Keywords:Analgesic, antagonist, IonWorks, screening protocol, sodium ion channel, state-dependence, use-dependence, NaV1.7 Antagonists, voltage condition, nerve cells
Abstract:Congenital Insensitivity to Pain (CIP) is a loss of function mutation resulting in a truncated NaV1.7 protein,
suggesting a pivotal role in pain signaling and rendering it an important pharmaceutical target for multiple pain
conditions. The structural homology in the NaV-channel family makes it challenging to design effective analgesic
compounds without inducing for example cardiotoxicity or seizure liabilities. An additional approach to structural isoform
selectivity is to identify compounds with use- or state-dependent profiles, i.e. inhibition efficacy based on the gating of the
ion channel. In general nerve cells in damaged or inflamed tissue are more depolarized and electrically active compared to
healthy nerve cells in for instance the heart. This observation has led to the design of two types of screening protocols
emulating the voltage condition of peripheral neurons or cardiac tissue. The two voltage protocols have been developed to
identify both use- and state-dependent antagonists. In this paper we describe an attempt to merge the two different
protocols into one to increase screening efficacy, while retaining relevant state- and use-dependent pharmacology. The
new protocol is constructed of two stimulation pulses and a slow voltage ramp for simultaneous assessment of resting and
state-dependent block. By comparing all protocols we show that the new protocol indeed filter compounds for statedependence
and increase the prediction power of selecting use-dependent compounds.
