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Novel HCN1-Selective Small Molecule Inhibitors for the Treatment of Neuropathic Pain
In the United States, at least 116 million adults suffer from chronic pain; the associated costs exceed $500 billion/yr. Neuropathic pain presents in 18% of chronic pain patients, and commonly arises from aberrant activity in the peripheral nervous system. chronic addiction, treatment Opioid analgesics are routinely prescribed for the treatment of pain but there are substantial risks involved with such therapy, including physical dependence, and fatal poisoning. The goal of this project is to develop a non-opioid antihyperalgesic for the of peripheral neuropathic pain. Neuronal hyperexcitability and spontaneous activity characterize neuropathic pain, properties associated with activity of hyperpolarization-activated, cyclic nucleotide-regulated (HCN1-4) channels, the source of the pacemaker current, Ih. Inhibition of HCN1-mediated Ih elicits marked antihyperalgesia in multiple animal models of neuropathic pain (including both direct nerve injury and chemotherapy-induced peripheral neuropathy, or CIPN), and does so with little or no disruption to either routine (normal) pain processing or baseline behaviors and activities. The overall objective is to develop a peripherally-restricted HCN1 inverse-agonist as a therapeutic for neuropathic pain. We have generated a novel small molecule (BP4L-18:1:1) that combines an antihyperalgesic HCN1 inhibitor with a motif that controls distribution and membrane presentation. Our immediate goal is to examine the behavior of BP4L-18:1:1 in detail and determine its efficacy and safety when administered orally as an antihyperalgesic in a rat model of nerve injury neuropathic pain. Our long-term goal is to determine if an injectable antibody-drug-conjugate (ADC)-derivative of BP4L-18:1:1, one that discretely targets peripheral HCN1 ion channels via association with an extracellular epitope on the channel, is safe and effective in relieving nerve injury and chemotherapy-induced neuropathic pain in appropriate rat models. Validation in these models will facilitate rapid transitioning to appropriate human studies. Successful completion of these goals will accelerate the development of an urgently needed, highly-effective, non-opioid, treatment for neuropathic pain.