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

• 批准号: 8358000
• 负责人: Bertha K Madras
• 金额: $ 1.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8358000
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Affect; Affinity; Binding; Cells; Central Nervous System Diseases; Cocaine Dependence; Corpus striatum structure; Dose; Drug Kinetics; Exhibits; Funding; Grant; Hour; Human; In Vitro; Injection of therapeutic agent; Macaca mulatta; Measures; National Center for Research Resources; New England; Norepinephrine; Pharmaceutical Preparations; Positron-Emission Tomography; Primates; Principal Investigator; Property; Research; Research Infrastructure; Resources; Route; Serotonin; Site; Source; Structure; Testing; Therapeutic; Therapeutic Uses; Time; United States National Institutes of Health; analog; base; cost; design; dopamine transporter; in vivo; inhibitor/antagonist; lipophilicity; monoamine; novel; pyrovalerone

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 目的：影响多巴胺转运蛋白（DAT）功能的化合物具有治疗可卡因成瘾和其他中枢神经系统疾病的治疗潜力。他们还具有滥用潜力，具体取决于结构，效力，剂量，药代动力学特性和给药途径。刺激性的吡喃酮是一种相对较高的亲和力DAT抑制剂，由于滥用责任，治疗用途有限。为了开发滥用责任降低的药物，我们设计了吡咯酮类似物，并评估了单胺转运蛋白（多巴胺，5-羟色胺，去甲肾上腺素）和DAT的体内占用率的体外效果。方法：在用人DAT转染的HEK-293细胞中确定数据亲和力。用DAT探针（11C）CFT（（（11C）WIN 35,428）和麻醉的恒河猴的PET成像测量了DAT占用（减少结合势）。在获得基线DAT级别后，对测试化合物进行了测试，并在一个小时后第二次注射（11C）CFT进行了PET成像。结果：新型的pyolovalerone类似物表现出高到中等的DAT效力（3.1-216 nm），并且中度至高DAT：SERT选择性。 所有化合物（1 mg/kg）占纹状体中59％或更多的DAT位点。在宠物会话的时间范围内，几种对DAT体外的高亲和力的化合物比低亲和力化合物显示出低的DAT占用率。 DAT占用与亲脂性（LOGP值）相关，而与DAT亲和力无关。结论：对于吡咯酮的类似物，亲脂性，但没有体外亲和力，可以预测体内DAT的占用率，几种化合物显示出快速的DATENSES，这对于治疗潜力或滥用责任都相关。