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

PROJECT SUMMARY/ABSTRACTIn 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.