A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability.
Br J Pharmacol
; 172(10): 2654-70, 2015 May.
Article
in En
| MEDLINE
| ID: mdl-25625641
ABSTRACT
BACKGROUND AND PURPOSE:
NaV 1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav 1.8 channel blocker of novel chemotype. EXPERIMENTALAPPROACH:
The inhibition of Nav 1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain. KEYRESULTS:
PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50 331 nM) and in recombinantly expressed h Nav 1.8 channels (IC50 196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav 1.5 channels (IC50 â¼10 µM) and 65-100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50 â¼10-18 µM). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448 nM, and the block of both human recombinant Nav 1.8 channels and TTX-R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF-01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models. CONCLUSIONS AND IMPLICATIONS Using PF-01247324, we have confirmed a role for Nav 1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav 1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Picolinic Acids
/
Sensory Receptor Cells
/
Sodium Channel Blockers
/
Nociception
Limits:
Animals
/
Humans
Language:
En
Journal:
Br J Pharmacol
Year:
2015
Document type:
Article
Affiliation country:
United kingdom