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:10709890
- 负责人:
- 金额:$ 34.94万
- 依托单位:
- 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:
- 关键词:AdultAdverse effectsAfferent NeuronsAgonistAntineoplastic AgentsBindingBiological AssayCardiacCardiovascular systemCell LineCellsCharacteristicsChemistryClinicalCryoelectron MicroscopyDangerousnessDevelopmentDiabetes MellitusDiseaseDockingDoseElectrophysiology (science)EnzymesFreedomGeneral anesthetic drugsGenerationsGoalsHCN1 channelHCN1 geneHCN4 geneHumanHydrocarbonsHyperalgesiaIn VitroIndividualInjuryIon ChannelLeadLegal patentLibrariesLicensingLigandsLipid BilayersMechanicsMedicineMembraneModelingMusNeuropathyNociceptionOpioid AnalgesicsOral AdministrationPacemakersPeripheralPeripheral Nervous SystemPeripheral nerve injuryPhasePhospholipidsPhysical DependencePoisoningPopulationPropertyPropofolProtein IsoformsPublic HealthQuality of lifeQuantitative Structure-Activity RelationshipRattusRightsRiskSafetySedation procedureSensorySiteSourceSpecificityStimulusStructureSurfaceTestingThermal HyperalgesiasToxic effectUnited StatesWorkabuse liabilityactive comparatoracute toxicityaddictionanalogchemotherapychronic painchronic pain managementchronic pain patientclinical developmentcostdesignhydrophilicityin silicoin vivoinhibitorlead optimizationmotor impairmentnanomolarnerve injurynew chemical entitynext generationnon-opioid analgesicnovelpainful neuropathypatch clamppharmacophorepredictive modelingquantumreceptorsmall molecule therapeuticsspared nervevirtual
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.
项目摘要/摘要
在美国,至少有1.16亿成年人患有慢性疼痛;相关成本超过500美元
10亿/年。神经病理性疼痛(与中枢和/或外周神经异常活动有关的慢性疼痛
系统)占慢性疼痛患者的18%。阿片类止痛药是常规处方用于
治疗慢性疼痛,但这种治疗有很大的风险,包括物理治疗
依赖、上瘾和致命的中毒。该项目的目标是优化活性药效团。
我们已确定的先导化合物的成分,并使用该新分子创建一种有效的非阿片类药物
用于治疗周围感觉神经病理性疼痛。
由电流引起的感觉神经元的过度兴奋与神经病理性疼痛有关。我们之前已经
证明了广泛使用和安全的全身麻醉剂异丙酚(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),
明显地保留了其他HCN亚型,包括形成心脏iH的那些(HCN4和2)。重要的是,SUB-
催眠药异丙酚和非麻醉剂2,6-二叔丁基苯酚(2,6-DTBP)抑制神经病理性痛敏
同时在很大程度上避免了正常的伤害性感受。
在这里,我们将在体外筛选一个受已知反向激动剂位点特性限制的化合物文库。
用于鉴定新的有效的、选择性的HCN1通道反向激动剂的烷基酚同系物;用于电子计算机模拟
预测和合成更多新的、有效的、对甲型H1N1流感有选择性的分子;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有效性和安全性。成功
拟议工作的完成将创造一种迫切需要的、高效的、非阿片类药物的治疗方法
神经性疼痛。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Steven R Fox', 18)}}的其他基金
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
- 批准号:
10545958 - 财政年份:2022
- 资助金额:
$ 34.94万 - 项目类别:
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