| Autor: |
Theile JW; Neusentis US, Pfizer Global R&D, (currently Icagen, Inc.), Durham, North Carolina jtheile@icagen.com., Fuller MD; Neusentis US, Pfizer Global R&D, (currently Icagen, Inc.), Durham, North Carolina., Chapman ML; Neusentis US, Pfizer Global R&D, (currently Icagen, Inc.), Durham, North Carolina. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular pharmacology [Mol Pharmacol] 2016 Nov; Vol. 90 (5), pp. 540-548. Date of Electronic Publication: 2016 Sep 01. |
| DOI: |
10.1124/mol.116.105437 |
| Abstrakt: |
Voltage-gated sodium (Na v ) channel inhibitors are used clinically as analgesics and local anesthetics. However, the absence of Na v channel isoform selectivity of current treatment options can result in adverse cardiac and central nervous system side effects, limiting their therapeutic utility. Human hereditary gain- or loss-of-pain disorders have demonstrated an essential role of Na v 1.7 sodium channels in the sensation of pain, thus making this channel an attractive target for new pain therapies. We previously identified a novel, state-dependent human Na v 1.7 selective inhibitor (PF-05089771, IC 50 = 11 nM) that interacts with the voltage-sensor domain (VSD) of domain IV. We further characterized the state-dependent interaction of PF-05089771 by systematically varying the voltage, frequency, and duration of conditioning prepulses to provide access to closed, open, and fast- or slow-inactivated states. The current study demonstrates that PF-05089771 exhibits a slow onset of block that is depolarization and concentration dependent, with a similarly slow recovery from block. Furthermore, the onset of block by PF-05089771 develops with similar rates using protocols that bias channels into predominantly fast- or slow-inactivated states, suggesting that channel inhibition is less dependent on the availability of a particular inactivated state than the relative time that the channel is depolarized. Taken together, the inhibitory profile of PF-05089771 suggests that a conformational change in the domain IV VSD after depolarization is necessary and sufficient to reveal a high-affinity binding site with which PF-05089771 interacts, stabilizing the channel in a nonconducting conformation from which recovery is slow.
(Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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