Understanding cardiac safety early is critical in drug development. In their latest poster, Jazz Pharmaceuticals, explain how they utilised Metrion’s clinically translatable cardiotoxicity assay to do exactly that.
Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels are a family of four non-selective cation channels (HCN1-4) that help regulate cardiac and neuronal rhythmicity. The HCN channels, differentially modulated by cyclic nucleotides, phosphorylation and neuromodulators, activate upon membrane hyperpolarisation, conducting inward K+ and Na+ currents to return cells to their resting membrane potential. HCN channel dysfunction has been associated with a range of neurological disorders including epilepsies, Parkinson’s Disease and pain1. Highly expressed in nociceptors, HCN2 has been implicated as a regulator of inflammatory and neuropathic pain. Inflammatory mediators increase neuronal cyclic adenosine monophosphate (cAMP) production, shifting HCN2 activation to more depolarised potentials, increasing the frequency of nociceptor firing. Currently, ivabradine is the only clinically approved HCN blocker used for treatment of chronic angina2. Ivabradine has been shown to reduce both inflammatory and neuropathic pain sensitivity in mouse models through reduced firing of peripheral nociceptors3. These findings highlight HCN2 as a potential nonopioid drug target in the treatment of chronic inflammatory and neuropathic pain.
Here, we demonstrate the generation and validation of a stable CHO-hHCN2 cell line used as a cellular tool in the successful development of hHCN2 automated electrophysiology screening assays. These assays create a platform for the screening of novel compounds to advance the development of selective hHCN2 modulators, useful in the treatment of pain.
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Understanding cardiac safety early is critical in drug development. In their latest poster, Jazz Pharmaceuticals, explain how they utilised Metrion’s clinically translatable cardiotoxicity assay to do exactly that.
Development of a robust hNaV1.9 high-throughput screening assay on the Sophion Qube384 platform. This is complemented by a suite of ion channel selectivity assays and sensory neuron recordings to create a versatile screening cascade to support NaV1.9 drug discovery programmes.