Completed Brain & Nervous System Heart, Stroke & Blood

Discovery and development of novel small molecule inhibitors of the human Hyperpolarizationactivated Cyclic Nucleotide-gated 2 (HCN2) ion channel for the treatment of inflammatory and neuropathic pain

Funder Wellcome Charity-funded
Associated organisations King's College London · University of Cambridge Europe PMC affiliations are not treated as award recipients or mapped locations.
Funding £2.9M
Period Jan 2014 — Mar 2021

In plain English

AI plain-English summary

A single protein in pain-sensing nerve cells is the target of a new drug discovery programme that aims to block both inflammatory and neuropathic pain at its source. Current pain treatments often fail or cause debilitating side effects. The problem is that many painkillers act broadly, hitting multiple targets throughout the body. Recent experiments show that deleting or blocking a specific ion channel called HCN2 in pain-sensitive neurons completely abolishes thermal inflammatory pain and all forms of neuropathic pain in mice. This suggests that a drug selective for HCN2—while avoiding the closely related HCN4 channel found in the heart—could provide effective pain relief without cardiac side effects. If successful, this project would produce an orally available, peripherally restricted compound that works in animal models of both pain types. The programme runs from initial hit generation through to late-stage lead optimisation, combining academic pain biology expertise with industrial medicinal chemistry and high-throughput drug screening. A parallel, independently funded study is already testing the clinically approved HCN blocker ivabradine in healthy volunteers and patients with neuropathic pain, providing an early read on whether this approach translates to humans.

View original technical description
Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Our aim is to capitalize on recent experiments from the McNaughton lab which show that targeted deletion or pharmacological block of Hyperpolarisation activated, Cyclic- Nucleotide modulated 2 (HCN2) ion channels in pain-sensitive neurons completely abolishes thermal IP and all modes of NP. These experiments, and other more recent data, strongly suggest that blockers selective for HCN2 over the cardiac isoform HCN4 will be effective in the treatment of both IP and NP. The project is a comprehensive programme from hit generation to a late stage in lead optimization which will identify orally available and peripherally restricted compounds with high selectivity for HCN2 and efficacy in mouse models of both IP and NP. The project will combine the McNaughton lab's expertise in the scientific basis of pain and in the implementation of animal models of pain with the medicinal chemistry expertise of Argenta and the highthroughput ion channel drug discovery platform of Millipore. In an independently funded parallel programme we will test the non-specific but clinically approved HCN blocker ivabradine for efficacy in both healthy human volunteer models of NP and in clinical NP patients.

View the original record at the funder ↗

Researchers

Peter McNaughton (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

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Role of HCN ion channels in pain
Role of HCN ion channels in neuropathic pain: a combined animal and human study
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Original classification

Seeding Drug Discovery Award

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.