Uncovering the roles of oxysterols in neuropathic pain
揭示氧甾醇在神经性疼痛中的作用
基本信息
- 批准号:10504409
- 负责人:
- 金额:$ 52.03万
- 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:2022-07-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnalgesicsAstrocytesBehavioralBiochemicalBiological AssayBiological AvailabilityCell LineageCellsChronicCoupledDataDevelopmentDiseaseDockingDoseDrug KineticsExtracellular Signal Regulated KinasesFemaleGenesHelping to End Addiction Long-termHypersensitivityIn SituIn VitroInjectionsIpsilateralKnockout MiceLigandsLinkMaintenanceMedicalMetabolicMicrogliaMissionMitogen-Activated Protein KinasesModelingMolecularMotorMusNational Institute of Mental HealthNervous System TraumaNeurogliaNeurotoxinsNociceptionOpioidOpioid ReceptorOralPainPersistent painPersonsPertussis ToxinPharmaceutical ChemistryPharmacologic ActionsPharmacologyPropertyProteinsPublicationsPublishingRattusReaction TimeReflex actionRewardsRodentRoleSignal TransductionSignaling MoleculeSiteSolubilitySpinalSpinal CordSpinal cord posterior hornStimulusStructure-Activity RelationshipSystemTestingTherapeutic InterventionTimeTissuesTranscriptTraumaTraumatic Nerve InjuryWithdrawalabsorptionallodyniaanalogantagonistbasebehavioral phenotypingbehavioral responsebehavioral studychemical propertychronic neuropathic paindesigndrug discoveryendogenous opioidsimprovedin silicoin vivointerdisciplinary approachmalenerve injuryneuroinflammationnon-opioid analgesicnovelp38 Mitogen Activated Protein Kinasepain modelpainful neuropathypharmacophorereceptorrelease of sequestered calcium ion into cytoplasmside effectsmall moleculetargeted treatmenttooltranscriptomics
项目摘要
Chronic neuropathic pain afflicts 15-20 million people in the U.S.1 Defining the molecular mechanisms involved
is key to developing novel non-opioid analgesics.2 We recently discovered that the Gαi protein-coupled receptor
(GPCR) Gpr183 transcript increases in glial cells of the dorsal horn of the spinal cord (DH-SC) following nerve
injury and contributes to ensuing neuropathic pain.3 The primary endogenous ligand for GPR183 is the potent
signaling oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC).4-6 However, little is known about the roles of 7α,25-
OHC/GPR183 in pain beyond our recent publication.3 Moreover, commercial GPR183 antagonists are very
limited and have chemical properties that raise questions about their in vivo utility.3,7 To address this, we initiated
an in silico drug discovery approach that screened 5.5 million commercial compounds with similarities to a
GPR183 pharmacophore model, then docked and ranked the highest similar docking scores.3 The top 16
compounds were tested in calcium mobilization (FLIPR) assays to identify several small-molecule selective
GPR183 antagonists with IC50 values in the nM range, exemplified by SAE-14.3 SAE-14 was counter-screened
against the GPCRome at NIMH PDSP8 with no significant activity for over 300 receptors. Systemic SAE-14
administration reversed mechano-and cold allodynia (behavioral hypersensitivities) induced by nerve injury in
male and female rodents with no observable side effects or engaging the endogenous opioid system.3 These
effects were mimicked by intrathecal (i.th.) injection of SAE-14, identifying the spinal cord as a potential site of
GPR183 antagonist action.3 Moreover, pain behavioral phenotypes were recapitulated by i.th. injection of 7α,25-
OHC or a fluorinated analog that activated Gαi/o-linked (pertussis toxin), GPR183-dependent mitogen-activated
protein kinase (MAPK) signaling (preliminary data). MAPK signaling in the DH-SC is crucial in regulating
neuroinflammatory/pro-nociceptive genes and maintaining persistent pain sensitization.9,10 GPR183-dependent
MAPK signaling was supported by unbiased transcriptomic analysis of the DH-SC from SAE-14-treated rats with
neuropathic pain (preliminary data). SAE-14 lacks sufficient metabolic stability and solubility/absorption
(preliminary data) and structure-activity relationship studies on SAE-14 are necessary for optimization and
discovery of druggable GPR183 antagonists. Based on our published work3 and preliminary data, we
hypothesize that 7α,25-OHC/GPR183 signaling in the DH-SC contributes to the development and maintenance
of neuropathic pain states. Proposed studies in Aim 1 will investigate the role of 7α,25-OHC/GPR183 on MAPK
activation and neuroinflammation in the DH-SC. Then in Aim 2, we will develop GPR183 antagonists based on
SAE-14 and use a testing funnel to screen to find those with optimal stability and bioavailability for in vivo
pharmacological profiling in rodent neuropathic pain models in Aim 3. Our findings will further our understanding
of GPR183 signaling in neuropathic pain and identify the first small molecule GPR183 antagonists with properties
suitable for non-addictive analgesics development addressing a key mission of the HEAL initiative.
慢性神经性疼痛困扰着美国 15-2000 万人1 定义所涉及的分子机制
是开发新型非阿片类镇痛药的关键。2 我们最近发现 Gαi 蛋白偶联受体
(GPCR) 神经后脊髓背角 (DH-SC) 神经胶质细胞中 Gpr183 转录物增加
损伤并导致随后的神经性疼痛。3 GPR183 的主要内源性配体是有效的
信号氧甾醇 7α,25-二羟基胆固醇 (7α,25-OHC).4-6 然而,人们对 7α,25- 的作用知之甚少。
OHC/GPR183 在疼痛方面的作用超出了我们最近发表的文章3。此外,商业 GPR183 拮抗剂非常有效。
有限且其化学特性引发了对其体内效用的质疑。3,7 为了解决这个问题,我们发起了
一种计算机药物发现方法,筛选了 550 万种与药物相似的商业化合物
GPR183药效团模型,然后对接并排名相似对接分数最高的3名前16名
在钙动员 (FLIPR) 测定中对化合物进行了测试,以鉴定几种小分子选择性
IC50 值在 nM 范围内的 GPR183 拮抗剂,例如 SAE-14.3 SAE-14 进行了反筛选
与 NIMH PDSP8 上的 GPCRome 相比,对 300 多种受体没有显着活性。系统性 SAE-14
给药可逆转由神经损伤引起的机械性和冷性异常性疼痛(行为超敏反应)
雄性和雌性啮齿动物没有可观察到的副作用或参与内源性阿片类药物系统。3 这些
通过鞘内 (i.th) 注射 SAE-14 来模拟效果,将脊髓确定为潜在的 SAE-14 部位
GPR183 拮抗剂作用。3 此外,i.th 概括了疼痛行为表型。注射7α,25-
OHC 或激活 Gαi/o 连接(百日咳毒素)、GPR183 依赖性促细胞分裂原激活的氟化类似物
蛋白激酶 (MAPK) 信号传导(初步数据)。 DH-SC 中的 MAPK 信号传导对于调节至关重要
神经炎症/促伤害基因并维持持续的疼痛敏化。9,10 GPR183 依赖性
MAPK 信号传导得到 SAE-14 治疗大鼠 DH-SC 的无偏转录组学分析的支持
神经性疼痛(初步数据)。 SAE-14 缺乏足够的代谢稳定性和溶解度/吸收
(初步数据)和SAE-14的构效关系研究对于优化和
发现可药物化的 GPR183 拮抗剂。根据我们发表的工作3和初步数据,我们
假设 DH-SC 中的 7α,25-OHC/GPR183 信号传导有助于发育和维持
神经性疼痛状态。目标 1 中拟议的研究将调查 7α,25-OHC/GPR183 对 MAPK 的作用
DH-SC 中的激活和神经炎症。然后在目标2中,我们将基于GPR183拮抗剂开发
SAE-14并使用测试漏斗筛选以找到体内具有最佳稳定性和生物利用度的化合物
目标 3 中啮齿类神经病理性疼痛模型的药理学分析。我们的发现将进一步加深我们的理解
神经性疼痛中 GPR183 信号传导的研究,并鉴定出第一个具有特性的小分子 GPR183 拮抗剂
适用于非成瘾性镇痛药的开发,以实现 HEAL 计划的关键使命。
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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Christopher K Arnatt其他文献
41 - Lysophosphatidylserine/GPR34 Signaling in Neuropathic Pain
41 - 神经病理性疼痛中的溶血磷脂酰丝氨酸/GPR34 信号通路
- DOI:
10.1016/j.jpain.2025.104837 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:4.000
- 作者:
Janaine P. Oliveira;Luigi Giancotti;Timothy Doyle;Isaac Readnour;Christopher K Arnatt;John Walker;Daniela Salvemini - 通讯作者:
Daniela Salvemini
Christopher K Arnatt的其他文献
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{{ truncateString('Christopher K Arnatt', 18)}}的其他基金
Uncovering the roles of oxysterols in neuropathic pain
揭示氧甾醇在神经性疼痛中的作用
- 批准号:
10659247 - 财政年份:2022
- 资助金额:
$ 52.03万 - 项目类别:
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