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

用于治疗周围神经性疼痛的 HCN1 选择性反向激动剂的优化

基本信息

批准号：
10545958
负责人：
Steven R Fox
金额：
$ 34.94万
依托单位：
AKELOS INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545958
关键词：
Adult Adverse effects Afferent Neurons Agonist Antineoplastic Agents Binding Biological Assay Cardiac Cardiovascular system Cell Line Cells Characteristics Chemicals Chemistry Clinical Cryoelectron Microscopy Dangerousness Development Diabetes Mellitus Disease Docking Dose Electrophysiology (science)Enzymes Freedom General anesthetic drugs Generations Goals HCN1 channel HCN1 gene HCN4 gene Human Hydrocarbons Hyperalgesia In Vitro Individual Injury Ion Channel Lead Legal patent Libraries Ligands Lipid Bilayers Mechanics Medicine Membrane Modeling Mus Neuropathy Nociception Opioid Analgesics Oral Pacemakers Peripheral Peripheral Nervous System Peripheral nerve injury Phase Phospholipids Physical Dependence Poisoning Population Property Propofol Protein Isoforms Public Health Quality of life Quantitative Structure-Activity Relationship Rattus Rights Risk Safety Sedation procedure Sensory Site Source Specificity Stimulus Structure Surface Testing Thermal Hyperalgesias Toxic effect United States Work abuse liability active comparator acute toxicity addiction analog base chemotherapy chronic pain chronic pain management chronic pain patient clinical development cost design hydrophilicity hypnotic in silico in vivo inhibitor lead optimization motor impairment nanomolar nerve injury next generation non-opioid analgesic novel painful neuropathy patch clamp pharmacophore predictive modeling quantum receptor small molecule therapeutics spared nerve virtual

项目摘要

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.

项目概要/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 美元十亿/年神经性疼痛（与中枢和/或周围神经异常活动相关的慢性疼痛）系统）占慢性疼痛患者的 18%。阿片类镇痛药通常用于以下情况：治疗慢性疼痛，但这种治疗存在很大的风险，包括身体风险依赖性、成瘾性和致命中毒。该项目的目标是优化活性药效基团我们确定的先导化合物的成分，并使用该新型分子来创造一种有效的非阿片类药物用于治疗周围感觉神经性疼痛的治疗剂。 Ih 电流驱动的感觉神经元过度兴奋会导致神经性疼痛。我们之前有过证明了广泛使用且安全的全身麻醉药丙泊酚（2,6-二异丙基苯酚）以及密切相关的类似物，是有效的 HCN1 反向激动剂（即，它们充当通道功能的抑制剂），明显保留其他 HCN 异构体，包括形成心脏 Ih 的异构体（HCN4 和 2）。重要的是，子催眠药异丙酚和非麻醉剂 2,6-二叔丁基苯酚 (2,6-DTBP) 可抑制神经性痛觉过敏同时很大程度上避免了正常的伤害感受。在这里，我们将在体外筛选受已知反向激动剂位点特征限制的化合物库烷基酚同系物，用于鉴定新型有效、选择性 HCN1 通道反向激动剂；在计算机建模中的使用预测并合成其他新颖、有效、HCN1 选择性分子；并进行体内研究使用这些新型化合物中两种最有效的来评估抗痛觉过敏的功效和安全性。成功的完成拟议的工作将为以下患者提供一种急需的、高效的、非阿片类药物的治疗方法神经性疼痛。