SYNTHETIC CHEMISTRY AND PHARMACOLOGY

合成化学与药理学

• 批准号: 6346070
• 负责人: PETER W SCHILLER
• 金额: $ 18.07万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6346070
• 关键词: analgesics; bioassay; blood brain barrier; drug design /synthesis /production; endogenous opioid; guinea pigs; hamsters; hydropathy; laboratory mouse; laboratory rabbit; laboratory rat; mass spectrometry; muscle contraction; obstetric anesthesia; opioid receptor; peptide analog; peptide chemical synthesis; pharmacokinetics; protein structure function; receptor binding; sheep; synthetic peptide

We propose to develop novel opioid peptide analogs and derivatives with minimal side effects for use in obstetric analgesia. The structural characteristics of the new compounds should be such that they (i) retain high selectivity for either mu or delta opioid receptors, (ii) are able to penetrate the blood-brain barrier (BBB) (systemic administration) or the dura mater (epidural administration), and (iii) cannot cross the placental barrier (PB). It is expected that analgesics with this kind of profile may be discovered through structural modifications that produce considerable variation in the physico-chemical properties of already existing, receptor-selective opioid peptides. As parent peptides we will use four mu-selective opioid tetra-and dipeptide agonists and two novel dipeptide delta agonists, all of which were recently developed in the P.I.'s laboratory. We intend to achieve better penetration of the BBB by rendering the peptides more lipophilic (passage via passive diffusion) or by increasing the number of positive charges they carry (passage via non- specific, absorptive endocytosis). It is expected that a certain degree of lipophilicity and/or a certain number and distribution of positive charges may enable a peptide analog to cross the BBB but not the PB. Lipophilicity will be enhanced through incorporation of highly hydrophobic, artificial amino acids into the peptide and/or attachment of lipophilic moieties to end groups, whereas positive charges will be introduced through N- or C- terminal extension with basic amino acids and/or through peptide bond reductions or reversals. The opioid receptor affinities and selectivities of the new analogs will be determined in binding assays based on displacement of mu-, delta- and k-selective radio-ligands from rat brain or guinea pig membrane binding sites. Opioid agonist contractions of the guinea pig ileum and of the vase deferentia of the mouse, rat, hamster and rabbit. The relative stability of the analogs against enzymatic degradation (rat brain peptidases) will be examined. Analgesic activities of the compounds will be determined in the mouse writhing assay, a test model permitting the detection of both peripheral and central atinocipeption, and in the mouse hot plate test which detects only centrally mediated analgesic effects. Promising compounds will be synthesized on a larger scale for pharmacological and pharmacokinetic studies using chronically-instrumented pregnant sheep model to be carried out in Dr. Szeto's laboratory. The same compounds will also be prepared in deuterated form as standards for quantitative MS analyses to be performed in Dr. Desiderio's laboratory.

我们建议开发新颖的阿片类肽类似物和衍生物 用于产科镇痛的最小副作用。结构 新化合物的特征应该使其（i）保留 MU或Delta阿片类受体的高选择性，（II）能够 穿透血脑屏障（BBB）（全身给药）或 硬脑膜（硬膜外给药）和（iii）无法越过胎盘 障碍（PB）。预计具有这种配置文件的镇痛药 可以通过产生的结构修改发现 已经存在的物理化学特性的差异很大 现有的，受体选择性的阿片类肽。作为父肽，我们将 使用四个MU选择性阿片类动物和二肽激动剂和两个小说 二肽三角洲激动剂，所有这些都最近在 P.I.的实验室。我们打算通过 使肽更多的亲脂性（通过被动扩散通过）或 通过增加他们携带的正电荷数量（通过非 - 通过 特异性，吸收性内吞作用）。预计会有一定程度的 亲脂性和/或正电荷的一定数量和分布 可以使肽类似物可以越过BBB，而不是PB。亲脂性 将通过掺入高度疏水的人造来增强 氨基酸进入肽和/或亲脂性部分的附着 最终组，而正电荷将通过n-或c-引入 带碱性氨基酸和/或通过肽键的末端延伸 减少或逆转。阿片受体亲和力和选择性 新类似物的结合测定法将根据 来自大鼠大脑的Mu-，delta和K-选择性无线电的位移 或豚鼠膜结合位点。阿片类药物激动剂收缩 豚鼠回肠和小鼠，大鼠，仓鼠和 兔子。类似物对酶促的相对稳定性 将检查降解（大鼠脑肽酶）。镇痛活动 该化合物将在鼠标扭动测定中确定 允许检测外围和中央的模型 在鼠标热板测试中，仅检测 集中介导的镇痛作用。有希望的化合物将是 大规模合成用于药理和药代动力学 使用慢性启发的怀孕绵羊模型的研究 在Szeto博士的实验室中。同样的化合物也将在 申请形式作为定量MS分析的标准 在Desiderio博士的实验室中。