SYNTHETIC CHEMISTRY AND PHARMACOLOGY

我们建议开发新的阿片肽类似物和衍生物， 用于产科镇痛的副作用最小。结构性 新化合物的特性应使它们（i）保留 对μ或δ阿片样物质受体的高选择性，（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）不能穿过胎盘 屏障（PB）。预期具有这种特性的镇痛药 可能是通过结构改变发现的， 已经存在的物理化学性质的相当大的变化 受体选择性阿片肽。作为亲本肽，我们将 使用四种μ-选择性阿片类四肽和二肽激动剂和两种新的 二肽δ激动剂，所有这些都是最近开发的， P.I.的实验室。我们打算通过以下方式更好地渗透BBB 使肽更具亲脂性（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- 特异性吸收性内吞作用）。预计在一定程度上， 亲油性和/或一定数量和分布的正电荷 可以使肽类似物穿过BBB而不是PB。亲油性 将通过引入高度疏水的人工 将氨基酸插入肽中和/或将亲脂部分连接到 端基，而正电荷将通过N-或C-引入。 用碱性氨基酸和/或通过肽键进行末端延伸 减少或逆转。阿片受体的亲和力和选择性 的新类似物将在结合试验中确定， 大鼠脑中μ-、δ-和k-选择性放射性配体的置换 或豚鼠膜结合位点。阿片类激动剂收缩 豚鼠回肠和小鼠、大鼠、仓鼠和 兔子类似物对酶的相对稳定性 将检查降解（大鼠脑肽酶）。镇痛活性 将在小鼠扭体试验中测定化合物的含量， 模型允许检测外周和中枢 在小鼠热板试验中， 中枢介导的镇痛作用。有前途的化合物将是 在药理学和药代动力学上大规模合成 使用慢性妊娠绵羊模型进行的研究 在司徒博士的实验室里同样的化合物也将在 氘代形式作为定量MS分析的标准品 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.