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:
- 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 LineCellsCharacteristicsChemicalsChemistryClinicalCryoelectron MicroscopyDangerousnessDevelopmentDiabetes MellitusDiseaseDockingDoseElectrophysiology (science)EnzymesFreedomGeneral anesthetic drugsGenerationsGoalsHCN1 channelHCN1 geneHCN4 geneHumanHydrocarbonsHyperalgesiaIn VitroIndividualInjuryIon ChannelLeadLegal patentLibrariesLigandsLipid BilayersMechanicsMedicineMembraneModelingMusNeuropathyNociceptionOpioid AnalgesicsOralPacemakersPeripheralPeripheral Nervous SystemPeripheral nerve injuryPhasePhospholipidsPhysical DependencePoisoningPopulationPropertyPropofolProtein IsoformsPublic HealthQuality of lifeQuantitative Structure-Activity RelationshipRattusRightsRiskSafetySedation procedureSensorySiteSourceSpecificityStimulusStructureSurfaceTestingThermal HyperalgesiasToxic effectUnited StatesWorkabuse liabilityactive comparatoracute toxicityaddictionanalogbasechemotherapychronic painchronic pain managementchronic pain patientclinical developmentcostdesignhydrophilicityhypnoticin silicoin vivoinhibitorlead optimizationmotor impairmentnanomolarnerve injurynext 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.
项目总结/文摘
项目成果
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Steven R Fox其他文献
Steven R Fox的其他文献
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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:
10709890 - 财政年份:2022
- 资助金额:
$ 34.94万 - 项目类别:
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