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

项目总结/摘要 在美国，至少有1.16亿成年人患有慢性疼痛;相关费用超过500美元 亿/年。神经性疼痛（与中枢和/或外周神经系统异常活动相关的慢性疼痛） 系统）占慢性疼痛患者的18%。阿片类镇痛药是常规处方， 治疗慢性疼痛，但这种治疗涉及大量风险，包括身体 依赖、成瘾和致命的中毒。本项目的目标是优化活性药效团 我们确定的先导化合物的成分，并使用这种新分子来创造一种有效的，非阿片类药物 用于治疗外周感觉神经性疼痛的治疗剂。 电流驱动的感觉神经元过度兴奋导致神经病理性疼痛。我们先前已经 证明了广泛使用和安全的全身麻醉剂丙泊酚（2，6-二异丙基苯酚），以及 密切相关的类似物是有效的HCN 1反向激动剂（即，它们作为通道功能的抑制剂）， 显著地保留其它HCN同种型，包括形成心脏Ih的那些（HCN 4和2）。重要的是，子 催眠药丙泊酚和非麻醉药2，6-二叔丁基苯酚（2，6-DTBP）抑制神经性痛觉过敏 同时在很大程度上保留了正常的伤害感受。 在这里，我们将在体外筛选受已知的反向激动剂位点特征限制的化合物文库。 烷基酚同系物用于鉴定新型强效、选择性HCN 1通道反向激动剂;计算机模拟的应用 预测并合成新的、有效的HCN 1选择性分子;并进行体内研究 使用这些新化合物中最有效的两种来评估抗痛觉过敏的功效和安全性。成功 完成拟议的工作将创造一个迫切需要的，高效的，非阿片类药物，治疗 神经性疼痛

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.