DOPAMINE TRANSPORTER OCCUPANCY BY NOVEL PYROVALERONE ANALOGS, A PET STUDY
新型吡咯戊酮类似物对多巴胺转运蛋白的占用,宠物研究
基本信息
- 批准号:8358000
- 负责人:
- 金额:$ 1.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-05-01 至 2012-04-30
- 项目状态:已结题
- 来源:
- 关键词:2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazoleAffectAffinityBindingCellsCentral Nervous System DiseasesCocaine DependenceCorpus striatum structureDoseDrug KineticsExhibitsFundingGrantHourHumanIn VitroInjection of therapeutic agentMacaca mulattaMeasuresNational Center for Research ResourcesNew EnglandNorepinephrinePharmaceutical PreparationsPositron-Emission TomographyPrimatesPrincipal InvestigatorPropertyResearchResearch InfrastructureResourcesRouteSerotoninSiteSourceStructureTestingTherapeuticTherapeutic UsesTimeUnited States National Institutes of Healthanalogbasecostdesigndopamine transporterin vivoinhibitor/antagonistlipophilicitymonoaminenovelpyrovalerone
项目摘要
This subproject is one of many research subprojects utilizing the resources
provided by a Center grant funded by NIH/NCRR. Primary support for the subproject
and the subproject's principal investigator may have been provided by other sources,
including other NIH sources. The Total Cost listed for the subproject likely
represents the estimated amount of Center infrastructure utilized by the subproject,
not direct funding provided by the NCRR grant to the subproject or subproject staff.
AIMS: Compounds that affect dopamine transporter (DAT) function have therapeutic potential to treat cocaine addiction, and other CNS disorders. They also have abuse potential, depending on structure, potency, dose, pharmacokinetic properties and route of administration. The stimulant pyrovalerone is a relatively high affinity DAT inhibitor with limited therapeutic use because of abuse liability. To develop medications with reduced abuse liability, we designed pyrovalerone analogs and assessed in vitro potencies at monoamine transporters (dopamine, serotonin, norepinephrine) and in vivo occupancy of the DAT. METHODS: DAT affinity was determined in HEK-293 cells transfected with the human DAT. DAT occupancy (reduction in binding potential) was measured with PET imaging of the DAT probe (11C)CFT ((11C)WIN 35,428) and anesthetized rhesus monkeys. After acquisition of baseline DAT levels, the test compound was administered and PET imaging performed with a second injection of (11C)CFT one hour later. RESULTS: Novel pyrovalerone analogs exhibited high to moderate DAT potency (3.1 - 216 nM) and moderate to high DAT:SERT selectivity. All compounds (1 mg/kg) occupied 59 percent or more of DAT sites in the striatum. Several compounds with high affinity for the DAT in vitro showed lower DAT occupancy than lower affinity compounds, within the time frame of the PET session. DAT occupancy correlated with lipophilicity (logP values) and not with DAT affinity. CONCLUSIONS: For pyrovalerone analogs, lipophilicity, but not in vitro affinity, predicts in vivo DAT occupancy, Several compounds displayed rapid DAT onset, findings relevant both for therapeutic potential or abuse liability.
这个子项目是利用这些资源的众多研究子项目之一
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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Bertha K Madras其他文献
Bertha K Madras的其他文献
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{{ truncateString('Bertha K Madras', 18)}}的其他基金
Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling
长期使用 THC 会引起青少年大脑多巴胺信号的明显变化
- 批准号:
9979805 - 财政年份:2017
- 资助金额:
$ 1.38万 - 项目类别:
Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling
长期使用 THC 会引起青少年大脑多巴胺信号的明显变化
- 批准号:
9308499 - 财政年份:2017
- 资助金额:
$ 1.38万 - 项目类别:
Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling
长期使用 THC 会引起青少年大脑多巴胺信号的明显变化
- 批准号:
10222631 - 财政年份:2017
- 资助金额:
$ 1.38万 - 项目类别:
A PET STUDY OF DOPAMINERGIC ACTIVITY WITH ARMODAFINIL
阿莫达非尼多巴胺能活性的宠物研究
- 批准号:
8357964 - 财政年份:2011
- 资助金额:
$ 1.38万 - 项目类别:
ADOLESCENT AND ADULT MICE RESPOND DIFFERENTLY TO METHAMPHETAMINE
青少年和成年小鼠对甲基苯丙胺的反应不同
- 批准号:
8357963 - 财政年份:2011
- 资助金额:
$ 1.38万 - 项目类别:
MDMA ELICITS DIFFERENT BEHAVIORS, GENE EXPRESSION IN ADOLESCENT, ADULT MICE
MDMA 在青少年和成年小鼠中引发不同的行为和基因表达
- 批准号:
8357965 - 财政年份:2011
- 资助金额:
$ 1.38万 - 项目类别:
SYNTHESIS, BIOLOGICAL ASSESSMENT OF CANDIDATE MEDICATIONS FOR STIMULANT ABUSE
兴奋剂滥用候选药物的合成和生物学评估
- 批准号:
8358001 - 财政年份:2011
- 资助金额:
$ 1.38万 - 项目类别:
METHAMPHETAMINE MODULATES AXONAL GUIDANCE MOLECULES IN MOUSE HIPPOCAMPUS
甲基苯丙胺调节小鼠海马体中的轴突引导分子
- 批准号:
8172878 - 财政年份:2010
- 资助金额:
$ 1.38万 - 项目类别:
PHENETHYLAMINE (PEA) AND ATTENTION DEFICIT HYPERACTIVITY DISORDER
苯乙胺 (PEA) 和注意力缺陷多动障碍
- 批准号:
8172880 - 财政年份:2010
- 资助金额:
$ 1.38万 - 项目类别:
Methamphetamine and neurodevelopment in adolescent and adult mice
甲基苯丙胺与青少年和成年小鼠的神经发育
- 批准号:
8048397 - 财政年份:2010
- 资助金额:
$ 1.38万 - 项目类别:
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