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BIOCHEMICAL CORE

生化核心

基本信息

批准号：
8025974
负责人：
TODD W VANDERAH
金额：
$ 36.91万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8025974
关键词：
Achievement Acute Acute Pain Affinity Agonist Animal Model Animals Area Behavioral Binding Binding Sites Biochemical Biological Biological Assay Bradykinin Bradykinin B2 Receptor Bradykinin Receptor Calcium Calcium Channel Cavia Cells Characteristics Chemistry Chronic Chronic inflammatory pain Complementary DNA Complex Data Data Analyses Dose Dyes Dynorphin A Dynorphins Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Ensure Equipment Evaluation Exhibits Feedback Fluo-3 Goals Human Human Resources Hyperalgesia Hypersensitivity IACUC In Vitro Inflammatory Inhibitory Concentration 50 Kallidin Label Lead Ligation Maintenance Measures Mechanics Mediating Medical Modeling Mus Naloxone Narcotic Antagonists Negative Reinforcements Neuropathy Opiates Opioid Opioid Receptor Pain Pathology Potassium Chloride Protocols documentation Quality of life Radiation Radiolabeled Rattus Reaction Time Regulation Route Screening procedure Sensory Thresholds Signal Transduction Spinal nerve structure Stimulus Structure-Activity Relationship Tail Testing Tissues Training Vas deferens structure Withdrawal analog base chronic neuropathic pain chronic pain deltorphin design drug discovery fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether ileum in vitro Assay in vitro Bioassay in vitro activity in vivo in vivo Model meetings novel novel strategies painful neuropathy prevent programs radiotracer receptor receptor binding subcutaneous voltage

项目摘要

by the Chemistry Core. These compounds will be designed as opioid agonists and bradykinin/dynorphin antagonists in order to produce potent and efficacious antinociception targeting the pathology of neuropathic pain while eliminating antinocicpetive tolerance. The Biochemical Core contains 7 aims that will test such novel compounds. The in vitro pharmacological data in particular will provide timely feedback to the Chemistry Core on the structure-activity relationship (SAR) to further inform chemistry design. The initial binding and functional characterization of all novel compounds (est. 20 to 50 compounds/year) is necessary and essential for target-based drug discovery. To identify lead compounds, we must evaluate their affinity at multiple opioid and bradykinin receptors, and their apparent biological activity at each of these receptors. Studies will include in vitro tissue assaysto determine agonist and antagonist activity as well as novel compound activity at calcium channles using calcium fluorimetric analysis in transfectd cells. We will use a number of in vivo animal models to identify whether such novel bi-functional compounds produce antinociception as well as antihyperalgesia in inflammatory and chronic pain states. Finally, in vivo studies will be performed to detemine whether such compounds will result in antinocicpetive tolerance. Overall, Studies will be performed to identify molecules with agonist activity at one receptor and concurrent antagonist actions at a second receptor. The biochemical core provides dedicated equipment, personnel and expertise in data analysis for the entire project. It serves to centralize the use and maintenance of shared equipment and the technical training of personnel to use these equipment, management and oversight of animal protocols required by IACUC and Radiation Control, as well as to ensure data and information sharing with the Chemistry Core and the other projects. The biochemical core will synergize with projects A, C and D by providing lead compounds to directly test their hypotheses. RELEVANCE (Seeinstructions): Inflammatory and chronic neuropathic pains are growing areas of unmet medical need. Clinically, chronic pain remains poorly controlled by available therapies and thus adversely impacts quality of life (Arner & Meyerson, 1988). One reason for this lack of effect is the absence of compounds that specifically target the pathology of neuropathic pain. The goal of the chemistry & biochemical core of this PPG are to synthesize and test compounds that result in potent and efficacious antinociception while eliminating tolerance. PROJECT/

通过化学核心这些化合物将被设计为阿片激动剂和缓激肽/强啡肽拮抗剂，以产生针对神经病理性疾病病理学的强效和有效的抗伤害感受疼痛，同时消除抗伤害耐受性。生化核心包含7个目标，将测试这些新的化合物。体外药理学特别是，数据将为化学核心提供关于结构-活性关系的及时反馈 (SAR)以进一步通知化学设计。所有新的化合物的初始结合和功能表征都是通过对这些化合物的初始结合和功能表征来确定的。化合物（est. 20至50种化合物/年）对于基于靶向的药物发现是必要的和必不可少的。到为了确定先导化合物，我们必须评估它们对多种阿片和缓激肽受体的亲和力，在这些受体上的明显生物活性。研究将包括体外组织分析以确定激动剂和拮抗剂活性以及新化合物对钙通道的活性转染细胞中的荧光分析。我们将使用一些体内动物模型来确定是否这种新的双功能化合物在炎性和非炎性疾病中产生抗伤害感受以及抗痛觉过敏，慢性疼痛状态最后，将进行体内研究，以确定这些化合物是否导致抗伤害耐受性。总体而言，将进行研究以鉴定具有激动剂的分子对一种受体的活性和对第二种受体的同时拮抗剂作用。生化核心为整个项目的数据分析提供专用设备、人员和专业知识。它用于集中共用设备的使用和维护，并对使用这些设备的人员进行技术培训 IACUC和辐射控制所要求的动物方案的设备、管理和监督，并确保与化学核心项目和其他项目共享数据和信息。的生物化学核心将与项目A、C和D协同作用，提供先导化合物，直接测试其假设相关性（参见说明）：炎症性和慢性神经性疼痛是未满足的医疗需求的增长领域。临床上，慢性可用的治疗方法对疼痛的控制仍然很差，从而对生活质量产生不利影响（Arner & Meyerson，1988）。这种缺乏效果的一个原因是缺乏特异性靶向药物的化合物。神经性疼痛的病理学。这个PPG的化学和生物化学核心的目标是合成以及产生强效和有效的抗伤害感受同时消除耐受性的测试化合物。项目/