The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel comprises four members (HCN1-4) that are expressed in the heart and nervous system — and while HCN4 is well understood to modulate heart rate and drive pacemaker activity, HCN2 has emerged as a promising target for pain management. To seize the potential of inhibiting the channel to relieve pain, Merck has tied up with King’s College London, hoping the collaboration will yield a potent new class of painkillers without the dangerous side-effects seen with prescription opioids.
While at the University of Cambridge Peter McNaughton discovered in 2011 the key role HCN2 plays in chronic pain — the protein can cause a continuous sensation of pain through the initiation of electrical signals in pain-sensitive nerve fibres. After moving to King’s, McNaughton conducted preclinical studies that showed blocking the activity of HCN2 in diabetic mice with neuropathic pain triggered an analgesic effect.
Despite measures to reduce the use of narcotic prescription painkillers and illicit opioids in the United States, the crisis of opioid abuse, misuse and addiction is ubiquitous. In response, drugmakers are working on developing painkillers that are as potent as opioids, sans the high-risk side-effects.
Under the deal with Merck $MRK, King’s and its partner Wellcome Trust are eligible to receive up to $340 million in development and sales milestones, as well as royalties if a drug is approved for use. Merck is in charge of preclinical work and conducting human trials — the trick will be to develop a drug that blocks the activity of HCN2 selectively, without disturbing HCN4, which drives the heartbeat.
The US drugmaker has also pledged further funding for research into the biological mechanisms of pain at the McNaughton lab at King’s. Meanwhile the Wellcome Trust has already poured in £4.5 million to fund HCN2 research.
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