NOVEL HYDROPHILIC PROLACTIN INHIBITING DOPAMINE AGONISTS

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。垂体肌前支 负责抑制催乳素的多巴胺受体在 血脑屏障。 因此，该项目建议合成更特定的多巴胺。 激动剂，经过改造以模仿受体上的多巴胺构象， 但缺乏麦角吲哚的部分。亲水性基团将加入 试图制造出只在血脑之外起作用的化合物 障碍。在这个项目的第一年，我们合成了一系列 缺乏麦角吲哚部分的苯喹啉类多巴胺激动剂。这个 β-旋光构型的二羟基化合物(羟基在 8，9位)被证明是有效的多巴胺激动剂 体外培养的兔眼上皮细胞抑制催乳素分泌的能力 脑垂体细胞。这些试剂还取代了结合在一起的~3H-螺环酮 脑垂体前叶的多巴胺受体呈双相变化 大多数多巴胺激动剂。在提案的第二年，我们将 通过以下方式检查这些制剂穿越血脑屏障的能力 它们在体内刺激二羟基苯乙酸(DOPAC)形成的能力 尾状核。代理的行动持续时间将被测试 通过它们在体内抑制MBH损伤大鼠的PRL分泌的能力。 在更新期间，将合成更多的化合物，其中 2-取代基将改变以影响亲脂性和 化合物的极性，并通过改善空间位阻来最大化效力 激动剂与受体的相互作用，目的是获得一种 强大但高极性的分子，不会穿过血脑 障碍。 这些试剂的整体疏水性将通过以下方式进行监测 它们的辛醇/水分配系数。新化合物将是 在放射性配基结合分析中，通过抑制催乳素的能力进行测试 分泌物，对于它们穿越血脑屏障的能力，以及对于 他们的行动期限。

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.