Targeting the NaV1.3 sodium channel in the development of novel treatments for neuropathic pain

Richard Davies, Marc Rogers, Lam Tang, Ray Tang, Dave Madge, Rob Pinnock & John Ford, Xention Discovery, Pampisford Park, Pampisford, Cambridge CB2 4EF, UK.

Neuropathic pain occurs in a wide range of patients, including those affected by diabetes, HIV, herpes, cancer and chemotherapy. The expression of several Nav genes are altered in animal models of neuropathic pain, but perhaps the most promising clinical target is Nav1.3, which is upregulated in the DRG, spinal cord, and thalamus, and underlies the increased firing in axotomised DRG neurons (Black et al., 1999). Significantly, antisense knockdown of Nav1.3 abrogates hyperexcitability and pain-related behaviours in rat models of neuropathic pain (Hains et al., 2003) whereas neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8 (Nassar et al., 2005). As existing treatments for neuropathic pain are inadequate due to poor efficacy tolerance, abuse liability and drug interactions, this major area of unmet clinical need could be well served by a drug selectively targeting the Nav1.3 channel.

Compounds from several proprietary libraries were screened yielding ~2,500 novel chemical entities that inhibit the Nav1.3 channel by >50% at 10 μM (e.g. pimozide 73.0±14.1%, loperamide 66.9±2.8%, terfenadine 52.1±2.4%; n=3). Tricyclic antidepressants and anticonvulsants that are used off-label to treat neuropathic pain selectively target the inactivated state of the Nav1.3 channel, producing greater block of currents evoked after, compared to before, a depolarizing prepulse to -60 mV (imipramine > desipramine > nortriptyline > amitriptyline, ratio of %inhibition from 1.53 to 1.20, n=6 at 10 μM). These drugs stabilize the inactivated state of sodium channels, shifting the inactivation curve to the left and slowing the rate of recovery from inactivation. In the case of the anticonvulsant lamotrigine (100 μM), the midpoint of the inactivation curve is shifted by -8 mV, and the single exponential describing recovery from inactivation at a holding potential of -80 mV increased from 4.6 to 8.5 msec. Using tailored voltage clamp protocols to promote drug binding to various conformational states of the sodium channel, enabled us to measure drug block of the open and inactivated Nav1.3 channel, as well as their use- and frequency-dependence. We are using this information-rich electrophysiology data as the main driver for lead optimization and exploitation of the structure-activity relationship of hit compounds, and their derivatives, directed towards developing high affinity antagonists that are selective for the inactivated state of the Nav1.3 channel.

Black, J.A. et al. (1999) J. Neurophysiol. 82,2776-2785.
Hains, B.C. et al. (2003) J. Neurosci 23,8881-8892.
Nassar, M.A. et al. (2005) Molecular Pain 1,24.