Institute of Nuclear Medicine


Development of Nav1.7 Selective Inhibitors as Pain Therapeutics

Elena Yiannakia, Carlos Perez Medinaa,b, Martin Koltzenburgc, Erik Årstada,b
aUCL Department of Chemistry, Gordon Street, WC1H 0AJ; b Institute of Nuclear Medicine, University College Hospital, 235 Euston Road, London NW1 2BU, UK; c UCL Institute of Neurology, Queen Square. London, WC1N 3BG

Pain affects more than 20% of the population worldwide. Despite many efforts, its efficient treatment remains a great unmet medical challenge. Pain sensations originate in nociceptors. These are peripheral sensory neurons the excitability of which is controlled by voltage gated sodium channels (VGSC, Nav).1 To date, nine different VGSC isoforms have been cloned for the mammalian nervous system. Recent pre-clinical and clinical studies validate Nav1.7 as one of the isoforms with a key role in the pathophysiology of pain.2 Currently marketed VGSC blockers non-selectively inhibit all VGSCs meaning low-systematically tolerable doses and hence limited therapeutic potential.

Our studies focus on developing new Nav1.7 selective inhibitors as the next generation analgesics with improved efficacy and reduced side effect profile. We have discovered a class of compounds that appears to selectively block pain signalling whilst leaving other sensory signalling largely unaffected. Structure-activity relationships are being elucidated via the design, synthesis and the in vitro characterisation of multiple structural analogues. Optimised structures have shown nanomolar activity for Nav1.7 and exhibit up to 80-fold selectivity amongst other isoforms. Members of the family have been found to selectively block the nociceptor-containing, myelinated C-fibres while leaving the smaller unmyelinated A-fibres, associated with motor control, completely unaffected.

Schematic representation of the sodium channel.

Schematic representation of the sodium channel.

References: 1Theile, J.W. et al., Frontiers in Pharmacology 2011, 2, 54; 2Amir, R. et al., J. Pain 2006, 7, S1.