NOVEL PROBES FOR THE STUDY OF 5-HT2R NEUROBIOLOGY
用于研究 5-HT2R 神经生物学的新型探针
基本信息
- 批准号:8467832
- 负责人:
- 金额:$ 14.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAgonistAnimalsBehavioralBenignBindingBiologicalBiologyBiomedical ResearchCell membraneCell modelCellsCellular biologyCharacteristicsChemistryClinicalClinical ResearchCocaineCocaine DependenceDataDevelopmentDimerizationEquilibriumExhibitsGenetic PolymorphismGenotypeGoalsHeterodimerizationHomodimerizationHumanIndividualInvestigationKnowledgeLengthLettersLifeLigandsLinkLocationMethodologyModelingMolecularMolecular BiologyNeurobiologyOrganismPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacotherapyPopulationProcessPsychopharmacologyPsychostimulant dependenceRelapseResearchRodentRoleSeriesSerotoninSystemTestingTherapeuticValidationWorkabstractingaddictionanalogbasecravingdesigndimerhigh riskinnovationinsightinterestknowledge basemolecular shapemonomernovelpre-clinicalreceptorstructural biologytherapeutic developmenttherapeutic targettooltreatment strategy
项目摘要
Emerging knowledge of the contribution of the serotonergic neurobiology of addiction can be utilized to
design new pharmacotherapies based upon serotonergic mechanisms. Preclinical findings strongly suggest
that a 5-HT2AR antagonist, a 5-HT2cR agonist or ligands with a combination of these actions might be a
useful approach to reduce craving and enhance abstinence in addiction. The goal of Project 3 of the
Translational Center for Serotonin and Stimulant Addiction (TCSSA) is to utilize medicinal chemistry
methodology to create a series of bivalent homodimers of two 5-HT2AR antagonist molecules or two 5-HT2cR
agonist molecules with the promise of increased selectivity for these receptors, as well as a series of bivalent
heterodimers containing a selective 5-HTaAR antagonist molecule and a 5-HT2CR agonist molecule. The
dimers will be based on the highly selective 5-HT^R antagonist M100907 and 5-HT2CR agonist WAY 470.
Given the limited knowledge of how 5-HT ligands interact with their respective receptors, two derivatives of
each molecule will be examined. These analogs will differ based upon the point of connection of the tether to
the molecule. Prior to synthesizing dimers linked at these locations, the corresponding monomer controls
possessing a model for the tether will be synthesized and evaluated to determine which locations of
attachment are benign. Project 3 will work closely with Core B to screen these new molecules for functional
activity at wild-type 5-HT^R and 5-HT2CR, as well as at 5-HT^R and 5-HT2CR with genetic polymorphisms
that characterize the cocaine-dependent population (Project 1). This discovery research will create important
mechanistic understanding of the serotonergic system and its role in addiction biology (with Core B, Project
2) and bring these together with clinical insights and facilitate "proof-of-concept" in humans (Project 1).
Project 3 represents a high risk/exploratory project and a translational bridge between human and animal
psychopharmacology, medicinal chemistry, molecular biology and pharmacology which allows the rational
design of new molecules and drives innovation at the interfaces of biology and chemistry as well as
biomedical and clinical research. With the knowledge gained during this developmental period, we will build
upon our new understanding of the molecular, cellular and structural biology of the 5-HT2AR and 5-HT2CR
and the emerging biology of dimerization in living systems to propose additional strategies for discovery.
Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currently
available. We will design and create new drugs with the promise to enhance abstinence and reduce relapse
in cocaine dependence.
关于成瘾的血清素能神经生物学贡献的新知识可用于
根据血清素能机制设计新的药物疗法。临床前研究结果强烈表明
5-HT2AR拮抗剂、5-HT2cR激动剂或具有这些作用组合的配体可能是
减少对成瘾的渴望和增强戒瘾的有用方法。项目3的目标
血清素和兴奋剂成瘾转化中心 (TCSSA) 将利用药物化学
创建两个 5-HT2AR 拮抗剂分子或两个 5-HT2cR 的一系列二价同二聚体的方法
激动剂分子,有望增加对这些受体的选择性,以及一系列二价
含有选择性5-HTaAR拮抗剂分子和5-HT2CR激动剂分子的异二聚体。这
二聚体将基于高选择性 5-HT^R 拮抗剂 M100907 和 5-HT2CR 激动剂 WAY 470。
鉴于对 5-HT 配体如何与其各自受体相互作用的了解有限,两种衍生物
每个分子都将被检查。这些类似物将根据系绳的连接点而有所不同
分子。在合成连接在这些位置的二聚体之前,相应的单体控制
拥有系绳模型的人将被合成和评估,以确定哪些位置
附件是良性的。项目 3 将与 Core B 密切合作,筛选这些新分子的功能
野生型 5-HT^R 和 5-HT2CR 的活性,以及具有遗传多态性的 5-HT^R 和 5-HT2CR 的活性
可卡因依赖人群的特征(项目 1)。这项发现研究将创造重要的
对血清素能系统及其在成瘾生物学中的作用的机制理解(核心 B,项目
2) 并将这些与临床见解结合起来,促进人类的“概念验证”(项目 1)。
项目 3 代表一个高风险/探索性项目以及人类和动物之间的转化桥梁
精神药理学、药物化学、分子生物学和药理学,使合理的
新分子的设计并推动生物学和化学领域的创新
生物医学和临床研究。凭借在此发展时期获得的知识,我们将建立
基于我们对 5-HT2AR 和 5-HT2CR 的分子、细胞和结构生物学的新认识
以及生命系统中二聚化的新兴生物学提出了额外的发现策略。
拉夫摘要。目前尚无有效且易于使用的药物来治疗兴奋剂成瘾
可用的。我们将设计和创造新药,有望增强戒瘾并减少复发
可卡因依赖。
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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SCOTT R GILBERTSON其他文献
SCOTT R GILBERTSON的其他文献
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{{ truncateString('SCOTT R GILBERTSON', 18)}}的其他基金
Pilot Scale Libraries Based on Biologically Active Scaffolds
基于生物活性支架的中试规模文库
- 批准号:
7758425 - 财政年份:2010
- 资助金额:
$ 14.64万 - 项目类别:
Pilot Scale Libraries Based on Biologically Active Scaffolds
基于生物活性支架的中试规模文库
- 批准号:
8076724 - 财政年份:2010
- 资助金额:
$ 14.64万 - 项目类别:
Pilot Scale Libraries Based on Biologically Active Scaffolds
基于生物活性支架的中试规模文库
- 批准号:
8272696 - 财政年份:2010
- 资助金额:
$ 14.64万 - 项目类别:
NOVEL PROBES FOR THE STUDY OF 5-HT2R NEUROBIOLOGY
用于研究 5-HT2R 神经生物学的新型探针
- 批准号:
7680203 - 财政年份:2008
- 资助金额:
$ 14.64万 - 项目类别:
NOVEL PROBES FOR THE STUDY OF 5-HT2R NEUROBIOLOGY
用于研究 5-HT2R 神经生物学的新型探针
- 批准号:
7390002 - 财政年份:2007
- 资助金额:
$ 14.64万 - 项目类别:
Synthesis of Pilot Libraries Based on Medicinal Relevant Scaffolds
基于药物相关支架的中试文库的合成
- 批准号:
7921279 - 财政年份:2006
- 资助金额:
$ 14.64万 - 项目类别:
Synthesis of Pilot Libraries Based on Medicinal Relevant Scaffolds
基于药物相关支架的中试文库的合成
- 批准号:
7487911 - 财政年份:2006
- 资助金额:
$ 14.64万 - 项目类别:
Synthesis of Pilot Libraries Based on Medicinal Relevant Scaffolds
基于药物相关支架的中试文库的合成
- 批准号:
7192186 - 财政年份:2006
- 资助金额:
$ 14.64万 - 项目类别:
Synthesis of Pilot Libraries Based on Medicinal Relevant Scaffolds
基于药物相关支架的中试文库的合成
- 批准号:
7287791 - 财政年份:2006
- 资助金额:
$ 14.64万 - 项目类别:
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