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A novel selective and orally bioavailable N a v 1.8 channel blocker, PF ‐01247324, attenuates nociception and sensory neuron excitability
Author(s) -
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,
Ban 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
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13092
Subject(s) - dorsal root ganglion , neuropathic pain , nociception , sodium channel , pharmacology , patch clamp , sodium channel blocker , channel blocker , chemistry , sensory neuron , tetrodotoxin , in vivo , electrophysiology , medicine , neuroscience , receptor , sensory system , biology , biochemistry , sodium , calcium , microbiology and biotechnology , organic chemistry
Background and Purpose N a 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 N a v 1.8 channel blocker of novel chemotype. Experimental Approach The inhibition of N a 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 50 : 331 nM ) and in recombinantly expressed h N a v 1.8 channels ( IC 50 : 196 nM ), with 50‐fold selectivity over recombinantly expressed TTX ‐ R h N a v 1.5 channels ( IC 50 : ∼10 μM ) and 65–100‐fold selectivity over TTX ‐sensitive ( TTX ‐ S ) channels ( IC 50 : ∼10–18 μM ). Native TTX ‐ R currents in small‐diameter rodent DRG neurons were inhibited with an IC 50 448 nM , and the block of both human recombinant Na 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 N a v 1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for N a v 1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.