SYNTHETIC CHEMISTRY AND PHARMACOLOGY

我们建议开发新的阿片肽类似物和衍生物 用于产科止痛的副作用最小。结构性的 新化合物的特性应使它们(I)保持 对Mu或Delta阿片受体具有高选择性，(Ii)能够 穿透血脑屏障(BBB)(全身给药)或 硬膜外注射(硬膜外注射)，以及(Iii)不能穿过胎盘 屏障(PB)。预计具有这种特征的止痛药 可能是通过结构修改发现的 已经存在的物理化学性质的相当大的变化 现有的受体选择性阿片肽。作为母体多肽，我们将 使用四种MU选择性阿片类四肽和二肽激动剂和两种新的 二肽三角洲激动剂，所有这些都是最近在 P.I.S实验室。我们打算通过以下方式更好地渗透血脑屏障 使多肽更具亲脂性(通过被动扩散)或 通过增加它们携带的正电荷的数量(通过非 特异的、可吸收的内吞作用)。预计会有一定程度的 亲油性和/或一定数量和分布的正电荷 可以使多肽类似物穿过血脑屏障，但不能穿过PB。亲脂性 将通过加入高度疏水的人造 氨基酸进入多肽和/或亲脂性部分附着到 端基，而正电荷将通过N-或C- 带有碱性氨基酸和/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 的新类似物将在结合分析中确定，基于 Mu、Delta和K选择性放射性配体在大鼠脑内的置换 或豚鼠细胞膜结合部位。阿片类激动剂收缩 豚鼠回肠和花瓶输精小鼠、大鼠、仓鼠和 兔子。类似物对酶的相对稳定性 将检测降解(大鼠脑多肽酶)。止痛活性 的化合物将在小鼠扭体试验中确定，这是一种测试 允许同时检测外周和中央的型号 抑制，并在小鼠热板试验中仅检测到 中枢介导的止痛作用。前景看好的化合物将是 更大规模的药理和药代动力学合成 慢性仪器化妊娠绵羊模型的研究 在司徒博士的实验室里。同样的化合物也将在 作为进行定量MS分析的标准的氢化形式 在德西德里奥博士的实验室里。

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.