Targeting Chronic Pain: The Therapeutic Potential of PF-01247324, a Selective NaV1.8 Channel Blocker

The study focuses on the development of a new, selective, and orally bioavailable drug named PF-01247324, which targets the NaV1.8 ion channel—a significant molecular target for treating chronic pain. The drug's inhibitory effects were examined through in vitro patch-clamp electrophysiology, establishing its oral bioavailability and pain-relieving properties in in vivo rodent models of inflammatory and neuropathic pain.

Key findings of the research indicate that PF-01247324 effectively inhibits tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons with an IC50 of 331 nM and in recombinantly expressed human NaV1.8 channels with an IC50 of 196 nM. It also showed a 50-fold selectivity over TTX-R human NaV1.5 channels and a 65-100 fold selectivity over TTX-sensitive (TTX-S) channels. In rodent DRG neurons, the drug inhibited TTX-R currents with an IC50 of 448 nM. The blockage of both human recombinant NaV1.8 channels and TTX-R from rat DRG neurons was found to be dependent on frequency and state. PF-01247324 was observed to reduce neuronal excitability and alter the action potential waveform in both rat and human DRG neurons. In vivo experiments confirmed the drug's efficacy in both types of pain models.

The research concludes that PF-01247324 confirms the role of NaV1.8 channels in inflammatory and neuropathic pain and highlights their importance in the action potential upstroke and repetitive firing of rat and human DRG neurons.