+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Identification of novel NaV1.7 antagonists using high throughput screening platforms

Identification of novel NaV1.7 antagonists using high throughput screening platforms

Combinatorial Chemistry and High Throughput Screening 15(9): 713-720

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 state-dependence and increase the prediction power of selecting use-dependent compounds.

Please choose payment method:

(PDF emailed within 1 workday: $29.90)

Accession: 053668517

Download citation: RISBibTeXText

PMID: 22934951

Related references

Platforms for high-throughput screening of Wnt/Frizzled antagonists. Drug Discovery Today 17(23-24): 1316-1322, 2013

Identification of acetylcholinesterase inhibitors using homogenous cell-based assays in quantitative high-throughput screening platforms. Biotechnology Journal 12(5), 2017

Identification of novel selective P2Y 6 receptor antagonists by high-throughput screening assay. Life Sciences 180: 137-142, 2017

Identification of two antagonists of the scavenger receptor CD36 using a high-throughput screening model. Analytical Biochemistry 400(2): 207-212, 2010

High-Throughput Screening by Nuclear Magnetic Resonance (HTS by NMR) for the Identification of PPIs Antagonists. Current Topics in Medicinal Chemistry 15(20): 2032-2042, 2016

Identification of small molecule NPR-B antagonists by high throughput screening--potential use in heart failure. Naunyn-Schmiedeberg's Archives of Pharmacology 387(1): 5-14, 2014

Identification of metabotropic glutamate receptor antagonists using an automated high-throughput screening system. Analytical Biochemistry 313(2): 246-254, February 15, 2003

High-throughput screening based identification of small molecule antagonists of integrin CD11b/CD18 ligand binding. Biochemical and Biophysical Research Communications 394(1): 194-199, 2010

High-throughput screening using beta-lactamase reporter-gene technology for identification of low-molecular-weight antagonists of the human gonadotropin releasing hormone receptor. Assay and Drug Development Technologies 3(2): 143-154, 2005

Discovery of novel inhibitors of Bcl-xL using multiple high-throughput screening platforms. Analytical Biochemistry 328(2): 131-138, 2004

High-throughput platforms for the screening of new therapeutic targets for neurodegenerative diseases. Drug Discovery Today 21(9): 1355-1366, 2018

Microfluidics for cell-based high throughput screening platforms - A review. Analytica Chimica Acta 903: 36-50, 2016

Pattern recognition analysis of endogenous cell metabolites for high throughput mode of action identification: removing the postscreening dilemma associated with whole-organism high throughput screening. Journal of Biomolecular Screening 5(5): 335-342, 2000

Screening plateletpheresis donors for HLA antibodies on two high-throughput platforms and correlation with recipient outcome. Transfusion 51(3): 504-510, 2011

Novel Phenotypic Fluorescent Three-Dimensional Platforms for High-throughput Drug Screening and Personalized Chemotherapy. Journal of Cancer 4(5): 402-415, 2013