Voltage-dependent sodium channels (Nav) are implicated in a wide range of diseases, with their role in triggering and modulating membrane excitability making them key drug discovery targets for cardiac and neurological indications. Neuronal Nav’s are divided into TTX-sensitive (Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7) and TTX-resistant channels (Nav1.8 and Nav1.9), with those found in the CNS underlying various types of epilepsy and those expressed in the periphery implicated in many types of pain behaviour such as inflammatory, neuropathic, chemotherapy and cancer-induced pain, as well as visceral pain conditions such as irritable bowel syndrome (IBS).

Rogers, M.; Zidar, N.; Kikelj, D.; Kirby, R.W. Assay and Drug Development Technologies. 2016, 14 (2),109-130

El-Haou, S.; Ford, J.; Milnes, J. Journal of Cardiovascular Pharmacology. 2015, 66 (5), 412-431

Presentation by Marc Rogers (Metrion CSO) at the September 2015 Safety Pharmacological Society, Prague. Using high quality HTS automated patch-clamp data from human cardiac ion channels and in silico action potential modelling to cost-effectively predict QP prolongation and arrhythmia risk for CiPA.

Current cardiac safety testing regimes have successfully prevented new drugs coming to market with unknown proarrhythmic risk. However, they are expensive and time-consuming, and an over-reliance on hERG liability as a marker for proarrhythmia has led to exclusion of useful chemical scaffolds from further drug development. In addition, the focus on hERG ignores the risk posed by potential drug interactions with multiple cardiac ion channels (MICE) that can alter cardiac action potentials.

The TTX-resistant sodium channel Nav1.8 is expressed in peripheral sensory nociceptors and is implicated in a range of inflammatory and visceral pain conditions such as irritable bowel syndrome (IBS)1. Nav1.8 channel function in sensory neurons changes after injury or inflammation, with a redistribution from the soma to axons and upregulated activity through inflammatory mediators and signalling pathways.

Devalla, H.D.; Schwach, V.; Ford, J.W.; Milnes, J.T.; El‐Haou, S.; Jackson, C.; Gkatzis, K.; Elliott, D.A.; de Sousa Lopes, S.M.C.; Mummery, C.L.; Verkerk, A.O.; Passier, R. EMBO Molecular Medicine 2015. 7 (4), 394-410

Jukič, M.; Frlan, R.; Chan, F.; Kirby, R.W.; Madge, D.J.; Tytgat, J.; Peigneur, S.; Anderluh, M.; Kikelj, D. Medicinal Chemistry Research. 2015, 24 (6), 2366-2380

Peigneur, S.; Žula, A.; Zidar, N.; Chan-Porter, F.; Kirby, R.; Madge, D.; Ilaš, J.; Kikelj, D.; Tytgat, J. Marine Drugs. 2014, 12(4), 2132-43