SELECTIVE FLUORESCENT PROBES FOR OPIOID RECEPTOR TYPES

这项研究的长期目标是开发选择性，荧光 δ、κ和μ阿片受体类型的探针。 探针将 被设计成使功能性阿片受体可以被可视化， 共聚焦激光扫描显微镜 这一目标将由 使用衍生自纳曲吲哚（δ）的选择性药效团， norbinaltorphimine（kappa）和羟吗啡酮和纳洛酮（mu）。 三 不同颜色的荧光团将附着在药效团上 通过策略性地放置亲水间隔物， 保留了配体的选择性和效力。 不同 彩色荧光团将被用于最终成像， 三种阿片受体同时存在 这些配体将是 在4种体外制剂中评价：豚鼠脑中的结合 豚鼠回肠中的膜、拮抗剂和激动剂效力， 小鼠输精管和三细胞共聚焦显微镜观察 群体（NG 108 -15，SH-SY 5 Y，豚鼠小脑），含有 定义阿片受体群体。 有希望的配体将经历 抗伤害性测试，并最终，从测试的神经组织 将检查动物以评价探针成像的能力 体内阿片受体群体。 实现这一长期目标 目标将提供选择性阿片受体探针的医疗设备， 扫描激光共聚焦显微镜

The long-term goal of this research is to develop selective, fluorescent probes for delta, kappa, and mu opioid receptor types. The probes will be designed so that functioning opioid receptors can be visualized using the confocal scanning laser microscope. This goal will be pursued by the use of selective pharmacophores derived from naltrindole (delta), norbinaltorphimine (kappa), and oxymorphone and naltrexone (mu). Three different colored fluorephores will be attached to the pharmacophores through strategically placed hydrophilic spacers so that affinity, selectivity, and potency of the ligands are retained. The different colored fluorephores will be employed in an effort to ultimately image three opioid receptor types simultaneously. These ligands will be evaluated in four in vitro preparations: binding in guinea pig brain membranes, antagonist and agonist potencies in the guinea pig ileum and mouse vas deferens, and confocal microscopic visualization in three cell populations (NG108-15, SH-SY5Y, guinea pig cerebellum) that contain defined opioid receptor populations. Promising ligands will then undergo antinociceptive testing and, ultimately, neural tissues from the tested animals will be examined to evaluate the ability of the probe to image opioid receptor populations in vivo. The attainment of this long-range goal will afford on armamentarium of selective opioid receptor probes for scanning laser confocal microscopy.