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: 3279855
• 负责人: JOHN C CRAIG
• 金额: $ 14.19万
• 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 1988-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3279855
• 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; tritium

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 pituitay dopamine receptors responsible for prolactin inhibition are outside the blood brain barrier. This project therefore 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 the blood brain barrier. During the first year of this project we synthesized a series of benzoquinolines as dopamine agonists lacking the ergot indole moiety. The dihydroxy compounds in the Beta-rotameric configuration (hydroxy groups in the 8,9 positions) were shown to be potent dopamine agonists by their ability to suppress prolactin (PRL) secretion in cultured anterior pituitary cells. These agents also displaced 3H-spiperone bound to anterior pituitary dopamine receptors in a biphasic fashion as observed for most dopamine agonists. During the second year of the proposal we will examine the ability of these agents to cross the blood brain barrier by their capacity to stimulate dihydroxyphenylacetic acid (DOPAC) formation in the caudate nucleus. The duration of action of the agents will be tested by their ability to suppress PRL secretion in vivo in MBH lesioned rats. During the renewal period additional compounds will be synthesized in which the 2-substituent will be varied to influence the lipophilicity and polarity of the compounds, and to maximize potency by improvng the steric interaction of the agonist with the receptor, with the goal of obtaining a potent but highly polar molecule which will not cross the blood brain barrier. The overall hydrophobicity of the agents will be monitored by determining their octanol/water partition coefficients. The new compounds will be tested in radio ligand binding assays, by their capacity to suppress PRL secretion, for their ability to cross the blood brain barrier, and for their duration of action.

尽管几种麦角衍生物在减少这两种疾病方面都是有效的， 垂体瘤体积和血清催乳素水平 高催乳素血症，使用这些药物往往伴随着 不良副作用。 这些影响可能是由于存在 药物分子中完整的麦角结构或 中枢神经系统内的多巴胺受体。 垂体前叶 负责催乳素抑制的多巴胺受体在 血脑屏障 因此，本项目提出合成更特异的多巴胺 激动剂，经修饰以模拟多巴胺在受体处的构象， 但缺少麦角吲哚部分。 亲水基团将被添加到 试图制造只在血脑外起作用的化合物 屏障 在这个项目的第一年，我们综合了一系列 苯并喹啉类作为缺乏麦角吲哚部分的多巴胺激动剂。 的 β-旋转异构体构型的二羟基化合物（ 8，9位）通过其 能够抑制催乳素（PRL）分泌的培养前 垂体细胞 这些药物还取代了与 垂体前叶多巴胺受体呈双相性， 大多数多巴胺激动剂。 在提案的第二年，我们将 检查这些药剂通过血脑屏障的能力， 他们的能力，刺激二羟基苯乙酸（DOPAC）的形成， 尾状核 将测试药剂的作用持续时间 通过它们抑制MBH损伤大鼠体内PRL分泌的能力。 在更新期间，将合成另外的化合物，其中 2-取代基将变化以影响亲油性， 极性的化合物，并最大限度地提高效力，通过提高空间位阻 激动剂与受体的相互作用，其目的是获得激动剂与受体的相互作用。 一种强效但高极性的分子，不会穿过血脑 屏障 试剂的总体疏水性将通过测定 辛醇/水分配系数。 新化合物将 在放射性配体结合试验中，通过其抑制PRL的能力进行测试 分泌，因为它们能够穿过血脑屏障， 其作用的持续时间。