SELECTIVE FLUORESCENT PROBES FOR OPIOID RECEPTOR TYPES

这项研究的长期目标是开发选择性的、荧光的 探测Delta、kappa和u阿片受体类型。探测器将是 被设计成功能阿片受体可以使用 共聚焦扫描激光显微镜。这一目标将通过使用 来自纳曲哚(Delta)的选择性药理作用， 去甲肾上腺素(Kappa)、羟吗啡酮和纳曲酮(Mu)。三 不同颜色的荧光团将附着在药效团上 通过有策略地放置亲水性间隔物， 保留了配体的选择性和有效性。不同的 彩色荧光团将被用来最终成像 三种阿片受体类型同时发生。这些配基将被评估 在四种体外制剂中：结合在豚鼠脑膜上， 豚鼠回肠和小鼠输精管中拮抗剂和激动剂的作用 输精管，以及三种细胞群的共聚焦显微镜观察 (NGL08-L5，SH-SY5Y，豚鼠小脑)，含有定义的阿片类药物 受体种群。有希望的配体随后将接受抗伤害作用 测试，最终，来自测试动物的神经组织将被 检查以评估该探针成像阿片受体的能力 活体内的种群。实现这一远景目标将使 用于扫描激光的选择性阿片受体探针库 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 pharmacopheres derived from naltrindole (delta), norbinaltorphimine (kappa), and oxymorphone and naltrexone (mu). Three different colored fluorophores 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 fluorophores will be employed in an effort to ultimately image three opioid receptor types simultaneously. These ligand 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 (NGl08-l5, 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 an armamentarium of selective opioid receptor probes for scanning laser confocal microscopy.