BIOCHEMICAL CORE

通过 化学核心。这些化合物将被设计为阿片类激动剂和缓激肽/强啡肽 以神经病理性为靶点产生强效抗伤害感受的拮抗剂 消除疼痛的同时消除对伤害的耐受性。 生化核心包含7个目标，将测试这些新的化合物。体外药理研究进展 特别是数据将及时向化学核心提供关于结构-活性关系的反馈 (SAR)，以进一步告知化学设计。所有小说的初始结合和功能表征 化合物(Est.20至50种化合物/年)是以靶向为基础的药物发现所必需和必不可少的。至 为了鉴定先导化合物，我们必须评估它们与多种阿片和缓激肽受体的亲和力，以及它们的 这些受体中每一个都有明显的生物活性。研究将包括体外组织分析，以确定 钙通道激动剂和拮抗剂活性及新化合物活性 转基因细胞的荧光分析。我们将使用一些活体动物模型来确定 这种新的双功能化合物在炎症和疼痛中产生抗伤害性和抗痛觉过敏 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会 导致抗伤害耐受性。总体而言，将进行研究以识别具有激动剂的分子 在一个受体上的活性和在第二个受体上的同时拮抗作用。生化核心 为整个项目提供数据分析方面的专用设备、人员和专业知识。它的作用是 集中使用和维护共享设备，并对使用这些设备的人员进行技术培训 IACUC和辐射控制要求的动物协议的设备、管理和监督，AS 并确保与化学核心和其他项目共享数据和信息。这个 生化核心将通过提供先导化合物来直接测试他们的项目A、C和D 假设。 相关性(请参阅说明)： 炎症性和慢性神经性疼痛是日益增长的未得到满足的医疗需求领域。临床上，慢性 现有治疗方法对疼痛的控制仍然很差，因此对生活质量产生不利影响(Arner& Meyerson，1988)。缺乏这种效果的原因之一是缺乏专门针对 神经病理性疼痛的病理学。这种PPG的化学和生化核心的目标是合成 并测试能够在消除耐受性的同时产生强大而有效的抗伤害性的化合物。 项目/

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/