Details

Autor(en) / Beteiligte

• Payne, Claire Elizabeth
• Brown, Adam R
• Theile, Jonathon W
• Loucif, Alexandre J C
• Alexandrou, Aristos J
• Fuller, Mathew D
• Mahoney, John H
• Antonio, Brett M
• Gerlach, Aaron C
• Printzenhoff, David M
• Prime, Rebecca L
• Stockbridge, Gillian
• Kirkup, Anthony J
• Bannon, Anthony W
• England, Steve
• Chapman, Mark L
• Bagal, Sharan
• Roeloffs, Rosemarie
• Anand, Uma
• Anand, Praveen
• Bungay, Peter J
• Kemp, Mark
• Butt, Richard P
• Stevens, Edward B

Titel

A novel selective and orally bioavailable Na sub(v)1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability

Ist Teil von

• British journal of pharmacology, 2015-05, Vol.172 (10), p.2654-2670

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Background and Purpose Na sub(V)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 Na sub(v)1.8 channel blocker of novel chemotype. Experimental Approach The inhibition of Na sub(v)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. Key Results PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC sub(50): 331nM) and in recombinantly expressed h Na sub(v)1.8 channels (IC sub(50): 196nM), with 50-fold selectivity over recombinantly expressed TTX-R hNa sub(v)1.5 channels (IC sub(50): 10 mu M) and 65-100-fold selectivity over TTX-sensitive (TTX-S) channels (IC sub(50): 10-18 mu M). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC sub(50) 448nM, and the block of both human recombinant Na sub(v)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 Na sub(v)1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Na sub(v)1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.