NOVEL HYDROPHILIC PROLACTIN INHIBITING DOPAMINE AGONISTS

新型亲水性催乳素抑制多巴胺激动剂

• 批准号: 3279854
• 负责人: JOHN C CRAIG
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 1985-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3279854
• 关键词: blood brain barrier; catecholamine inhibitor; conformation; dopamine; drug administration routes; drug design /synthesis /production; drug metabolism; endocrine pharmacology; hormone inhibitor; membrane activity; prolactin; tissue /cell culture

Although several ergot derivatives have been effective in reducing both the volume of pituitary tumors and the serum prolactin level in hyperprolactinemia, the use of these drugs is often accompanied by undesirable side effects. These effects are possibly due to the presence of the intact ergot structure in the drug molecules or to actions at dopamine receptors within the central nervous system. Anterior pituitary dopamine receptors responsible for prolactin inhibition are outside the blood brain barrier. This project proposes the synthesis of more specific dopamine agonists (modified to mimic the conformation of dopamine at the receptor, but lacking the ergot indole moiety). Hydrophilic groups will be added in an attempt to produce compounds which only act outside of the blood brain barrier. New agents will be characterized by their ability to compete for 3H-spiperone or 3H-domperidone bound to membrane preparations of the anterior pituitary. Two such compounds have been synthesized to test our hypothesis. The first has been found to be equipotent with dopamine in competing for 3H-domperidone binding, with an IC50 of 100 nM, while the second is more than ten times as active, with an IC50 of 10 nM. Binding potencies will be compared to the ability of agents to suppress prolactin secretion from cultured anterior pituitary cells. The ability of compounds to cross the blood brain barrier will be determined by comparing their effects on rotational behavior following either intravenous or intraventricular administration. Dopamine receptors involved in rotational behavior lie within the blood brain barrier.

尽管几种麦角衍生品已经有效地降低了 脑垂体瘤体积与血清催乳素水平 高催乳素血症，这些药物的使用往往伴有 不良副作用。这些影响可能是由于 药物分子中完整的麦角结构或对药物的作用 中枢神经系统内的多巴胺受体。垂体前叶 负责抑制催乳素的多巴胺受体在 血脑屏障。 该项目建议合成更特定的多巴胺激动剂。 (经过修改以模仿受体上的多巴胺构象，但 缺乏麦角吲哚部分)。亲水性基团将被添加到 试图制造出只在血脑之外起作用的化合物 障碍。新代理商的特点是他们有能力竞争 ~3H-螺环酮或~3H-多潘立酮结合在小鼠的膜制剂上 脑下垂体前叶。已经合成了两个这样的化合物来测试我们的 假设。第一种已被发现与多巴胺在 竞争~3H-多潘立酮结合，IC_(50)为100纳米，而 第二个是活性的十倍以上，IC50为10 NM。装订 效力将与药物抑制催乳素的能力进行比较 培养的垂体前叶细胞的分泌物。化合物的能力 是否通过血脑屏障将通过比较他们的 静脉注射或静脉注射对旋转行为的影响 脑室内给药。参与旋转运动的多巴胺受体 行为存在于血脑屏障内。