PEPTIDES AS CENTRALLY OR PERIPHERALLY ACTING ANALGESICS

我们建议开发高μ受体选择性阿片肽类似物 其在相对亲脂性/亲水性方面显示出很大的多样性 他们的结构。 亲脂性类似物有望通过血液- 外周给药后一定程度上破坏了脑屏障（BBB）， 而极性类似物的作用将限于外围。 因此，所提出的类似物可作为新的镇痛剂， 中枢或外周介导的抗伤害感受。 外周诱导 镇痛是相当感兴趣的，因为阿片类药物的一些副作用 （呼吸抑制、附加责任等）被认为是 中枢介导的 一定的亲脂性/亲水性平衡可 允许类似物穿过BBB但不穿过胎盘 屏障，这样的类似物可能有潜力用于产科 analgesia. 为了实现这些目标，我们将使用跨学科的 方法结合有机化学，肽合成和广泛的 药理学特征 一种有效的亲脂性类似物（H-Tyr-D-Ala- Phe-Phe-NH 2）和极性原型类似物（Tyr-D-Arg-Phe-Lys-NH 2），两者均 显示出高的μ受体选择性，将作为先导化合物， 分别开发具有高亲脂性或极性特征的类似物。 所提出的肽类似物的设计将包括以下取代： 不寻常的氨基酸，肽键修饰和构象 限制性（环状）类似物。 的受体亲和力和选择性， 新的类似物将在基于置换的结合测定中确定 大鼠脑或豚鼠的μ、δ和κ选择性放射性配体 猪脑膜结合位点。 新的阿片激动剂活性 化合物将在体外基于抑制 电诱发豚鼠回肠和血管收缩 小鼠、大鼠、仓鼠和兔的生殖器。 相对稳定 抗酶降解（鼠脑肽酶）的类似物将 接受检查。 化合物的镇痛活性将在下文中测定。 小鼠扭体试验，一种允许检测 外周抗伤害感受，以及在小鼠热板试验中， 只有中枢作用的阿片类药物 外周介导的 将用季铵化阿片剂证明镇痛作用 对手。 阿片肽的胎盘转移和胎儿效应 类似物将使用长期仪器化的孕妇来确定。 绵羊模型

We propose to develop highly mu receptor-selective opioid peptide analogs that display great diversity in the relative lipophilicity/hydrophilicity of their structures. Lipophilic analogs are expected to cross the blood- brain barrier (BBB) to some extent after peripheral administration, whereas the action of polar analogs will be limited to the periphery. Thus, the proposed analogs may serve as novel analgesics producing either centrally or peripherally mediated antinociception. Peripherally induced analgesia is of considerable interest, since some side effects of opioids (respiratory depression, addition liability, etc.) are thought to be centrally mediated. A certain lipophilicity/hydrophilicity balance may permit analogs to penetrate across the BBB but not across the placental barrier, and such analogs may have potential for use in obstetric analgesia. To reach these goals, we will use an interdisciplinary approach incorporating organic chemistry, peptide synthesis and extensive pharmacologic characterization. A potent lipophilic analog (H-Tyr-D-Ala- Phe-Phe-NH2) and a polar prototype analog (Tyr-D-Arg-Phe-Lys-NH2), both showing high mu receptor selectivity, will serve as lead-compounds to develop analogs with high lipophilic or polar character, respectively. The proposed design of peptide analogs will include substitution of unusual amino acids, peptide bond modifications and conformationally restricted (cyclic) analogs. The receptor affinities and selectivities of the new analogs will be determined in binding assays based on displacement of mu, delta- and kappa-selective radioligands from rat brain or guinea pig brain membrane binding sites. Opioid agonist activities of the new compounds will be evaluated in vitro in bioassays based on inhibition of electrically evoked contractions of the guinea pig ileum and of the vasa 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 peripheral antinociception, and in the mouse hot plate test which detects only centrally acting opioids. The occurrence of peripherally mediated analgesic effects will be demonstrated with quaternized opiate antagonists. Placental transfer and fetal effects of the opioid peptide analogs will be determined using the chronically-instrumented pregnant sheep model.