5-HT2C Receptor PAMs as Neurotherapeutics for Cocaine Use Disorder
5-HT2C 受体 PAM 作为可卡因使用障碍的神经治疗药物
基本信息
- 批准号:9884750
- 负责人:
- 金额:$ 3.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-03-01 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAddressAffinityAgonistAlcoholsAllosteric SiteBehavior TherapyBehavioralBindingBiologicalBiological AssayCalciumCellsCharacteristicsChemicalsChinese Hamster Ovary CellClinicalCocaine DependenceDataDevelopmentDiglyceridesDiseaseDrug DesignDrug KineticsDrug Use DisorderExhibitsExperimental DesignsFDA approvedFamilyFluorineFosteringFunctional disorderG-Protein-Coupled ReceptorsGoalsHTR2A geneHeadHigh Pressure Liquid ChromatographyIn VitroInositolInterventionIntuitionKnowledgeLeadLigandsMass Spectrum AnalysisMedialMediatingMental disordersMetabolismMolecularMolecular ConformationNMR SpectroscopyNeurobiologyNeuropharmacologyNeurosciencesNeurotransmittersNicotineOpioidOrganic ChemistryPathologicPathologic ProcessesPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacotherapyPhenotypePhospholipasePlayPositron-Emission TomographyPre-Clinical ModelPrefrontal CortexPropertyPsychostimulant dependencePublic HealthRadiolabeledReceptor SignalingRelapseResolutionRoleSerotoninSerotonin Receptor 5-HT2BSerotonin Receptor 5-HT2CSignal TransductionSiteStructureStructure-Activity RelationshipSystemTailTechnical ExpertiseTherapeuticTracerWorkanalogbasebehavioral phenotypingclinically relevantcocaine usecomputational chemistrycounterscreendesigndrug candidatedrug discoverydrug of abuseeffective interventionexperienceexperimental studyflexibilityimprovedin vivoinnovationinsightinstrumentationlead optimizationlipophilicitynovelnovel lead compoundpositive allosteric modulatorpre-clinicalpreclinical developmentpreservationradioligandreceptorreceptor functionserotonin receptortherapeutic candidatetooltripolyphosphate
项目摘要
PROJECT SUMMARY
The serotonin (5-HT) neurotransmitter system comprises at least 14 distinct receptors that share topologically
similar orthosteric sites, a fact that contributes to the historically difficult goal of sub-type selective modulation.
Allosteric modulation of G protein-coupled receptors (GPCRs) can yield drug candidates for previously elusive
receptors through targeting a structurally divergent allosteric site. Evidence suggests that dysregulated signaling
of the 5-HT2C receptor underlies pathological processes implicated in numerous mental health disorders,
including cocaine use disorder, which is without an FDA-approved medication. Interestingly, reduced 5-HT2C
receptor signaling plays a modulatory role in stimulating relapse-related phenotypes in preclinical models of
cocaine addiction, and conversely, rescuing this dysfunction may provide clinical utility to promote and maintain
abstinence. We hypothesize that the rational design of novel 5-HT2C receptor positive allosteric modulators
(PAMs) and optimization of 5-HT2C receptor PAM lead compounds will serve as a useful strategy to rescue
pathologically decreased 5-HT2C receptor signaling and, ultimately, suppress relapse-related behavioral
phenotypes. To this end, 4-alkylpiperidine-2-carboxamides were designed and synthesized in a PAM hit-to-lead
discovery effort. The work resulted in the discovery of two novel lead compounds, which displayed subtype-
selective functional enhancement of the 5-HT2C receptor, and lacked intrinsic agonism, in vitro. Leads, CTW0415
and CYD-6-2-1, exhibited favorable in vitro and in vivo pharmacokinetics, while a broad-panel GPCR screen
confirmed selectivity. In addition, these leads maintain adequate lead-like physicochemical characteristics and
represent ideal molecules upon which to build our lead optimization efforts. Our iterative strategy for 5-HT2C
receptor PAM lead optimization will enable robust structure activity relationship (SAR) and will be accomplished
by 1) rational design and synthesis of novel 5-HT2C receptor selective PAMs; and 2) biological characterization
in a cell-based 5-HT2C receptor functional assay and pharmacological characterization in a radioligand binding
assay. The proposed work will advance our knowledge of 5-HT2C receptor positive allosteric modulation and
provide insight towards PAM mechanism. Additionally, the current PAM lead compounds require activity
enhancements via optimization to enable development of preclinical candidates. The completion of this proposal
will foster technical expertise and scientific intuition, ultimately enabling the applicant to achieve the goal of
becoming an academic chemical biologist studying drug use disorders and the neuropharmacology of drugs of
abuse. The applicant will gain experience in medicinal, organic and computational chemistry; neuroscience;
molecular and cellular pharmacology; GPCR targeting experimental design; and the fundamentals of drug
discovery in allosteric modulation, neurobiology and the psychostimulant addiction fields. Taken together, the
present studies represent a high impact approach towards the discovery of neurotherapeutics for cocaine use
disorder, and will generate novel tools to elucidate 5-HT2C receptor function and potential therapeutic candidates.
项目概要
血清素 (5-HT) 神经递质系统包含至少 14 个共享拓扑的不同受体
相似的正位点,这一事实有助于实现亚型选择性调制的历史上困难的目标。
G蛋白偶联受体(GPCR)的变构调节可以产生以前难以捉摸的候选药物
通过靶向结构不同的变构位点来识别受体。有证据表明,信号传导失调
5-HT2C 受体的功能是与许多精神健康障碍有关的病理过程的基础,
包括可卡因使用障碍,这是未经 FDA 批准的药物。有趣的是,减少了 5-HT2C
受体信号传导在刺激临床前模型中的复发相关表型中发挥调节作用
可卡因成瘾,相反,挽救这种功能障碍可能会提供临床实用性以促进和维持
节制。我们假设新型 5-HT2C 受体正变构调节剂的合理设计
(PAM) 和 5-HT2C 受体 PAM 先导化合物的优化将作为拯救的有用策略
病理性降低 5-HT2C 受体信号传导,最终抑制复发相关行为
表型。为此,在 PAM hit-to-lead 中设计并合成了 4-烷基哌啶-2-甲酰胺
发现努力。这项工作发现了两种新型先导化合物,它们显示出亚型-
在体外,选择性增强 5-HT2C 受体的功能,并且缺乏内在的激动作用。线索,CTW0415
和 CYD-6-2-1,表现出良好的体外和体内药代动力学,而广泛的 GPCR 筛选
证实了选择性。此外,这些引线保持了足够的类似引线的物理化学特性,并且
代表了我们构建先导优化工作的理想分子。我们的 5-HT2C 迭代策略
受体 PAM 先导化合物优化将实现稳健的结构活性关系 (SAR),并将实现
1)合理设计并合成新型5-HT2C受体选择性PAM; 2) 生物学特性
基于细胞的 5-HT2C 受体功能测定和放射性配体结合的药理学表征
化验。拟议的工作将增进我们对 5-HT2C 受体正变构调节和
提供对 PAM 机制的见解。此外,目前的 PAM 先导化合物需要活性
通过优化进行增强,以实现临床前候选药物的开发。本提案的完成情况
将培养技术专长和科学直觉,最终使申请人能够实现以下目标
成为一名研究药物使用障碍和药物神经药理学的学术化学生物学家
虐待。申请人将获得药物、有机和计算化学方面的经验;神经科学;
分子和细胞药理学; GPCR靶向实验设计;以及药物的基础知识
在变构调节、神经生物学和精神兴奋剂成瘾领域的发现。综合起来,
目前的研究代表了发现可卡因使用神经治疗药物的一种具有高影响力的方法
紊乱,并将产生新的工具来阐明 5-HT2C 受体功能和潜在的治疗候选者。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Eric A. Wold其他文献
Smal-molecule inhibitors targeting the canonical WNT signaling pathway for the treatment of cancer
- DOI:
doi.org/10.1021/acs.jmedchem.0c01799 - 发表时间:
2021 - 期刊:
- 影响因子:7.3
- 作者:
Zhiqing Liu;Pingyuan Wang;Eric A. Wold;Qiaoling Song;Chenyang Zhao;Changyun Wang;Jia Zhou - 通讯作者:
Jia Zhou
Eric A. Wold的其他文献
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