# Optimization of an HCN1-Selective Inverse Agonist for the Treatment of Peripheral Neuropathic Pain

> **NIH NIH R42** · AKELOS INC. · 2022 · $349,409

## Abstract

PROJECT SUMMARY/ABSTRACT
 In the United States, at least 116 million adults suffer from chronic pain; the associated costs exceed $500
billion/yr. Neuropathic pain (chronic pain associated with aberrant activity in the central and/or peripheral nervous
system) accounts for 18% of patients with chronic pain. Opioid analgesics are routinely prescribed for the
treatment of chronic pain but there are substantial risks involved with such therapy, including physical
dependence, addiction, and fatal poisoning. The goals of this project are to optimize the active pharmacophore
component of our identified lead compound and use that novel molecule to create a potent, non-opioid
therapeutic for the treatment of peripheral sensory neuropathic pain.
 Ih current-driven hyperexcitability in sensory neurons contributes to neuropathic pain. We have previously
demonstrated that the widely used and safe general anesthetic propofol (2,6-di-iso-propylphenol), as well as
closely related analogues, are potent HCN1 inverse agonists (i.e., they act as inhibitors of channel function),
markedly sparing other HCN isoforms including those that form cardiac Ih (HCN4 and 2). Importantly, sub-
hypnotic propofol and the non-anesthetic 2,6-di-tert-butylphenol (2,6-DTBP) suppress neuropathic hyperalgesia
while largely sparing normal nociception.
 Here we will screen in vitro a compound library constrained by known inverse agonist-site characteristics of
alkylphenol congeners to identify novel potent, selective HCN1 channel inverse agonists; use in silico modeling
to predict and then synthesize additional novel, potent, HCN1-selective molecules; and conduct in vivo studies
using the two most potent of those novel compounds to assess anti-hyperalgesic efficacy and safety. Successful
completion of the proposed work will create an urgently needed, highly-effective, non-opioid, treatment for
neuropathic pain.

## Key facts

- **NIH application ID:** 10545958
- **Project number:** 1R42NS129370-01
- **Recipient organization:** AKELOS INC.
- **Principal Investigator:** Steven R Fox
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,409
- **Award type:** 1
- **Project period:** 2022-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10545958

## Citation

> US National Institutes of Health, RePORTER application 10545958, Optimization of an HCN1-Selective Inverse Agonist for the Treatment of Peripheral Neuropathic Pain (1R42NS129370-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10545958. Licensed CC0.

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