PEPTIDES AS CENTRALLY OR PERIPHERALLY ACTING ANALGESICS

我们建议开发高度Mu受体选择性的阿片肽类似物 在相对亲油性/亲水性方面表现出很大的多样性 它们的结构。亲脂的类似物预计会通过血液- 外周给药后一定程度上的脑屏障(BBB)， 然而，极地类比的作用将局限于外围。 因此，所提出的类似物可用作新型镇痛剂，产生 中枢或外周介导的抗伤害性感觉。外围设备诱导 由于阿片类药物的一些副作用，人们对止痛很感兴趣 (呼吸抑制、附加责任等)被认为是 集中调停。一定的亲油性/亲水性平衡可以 允许类似物穿过血脑屏障，但不能穿过胎盘 屏障，这种类似物可能有潜力用于产科 止痛药。为了实现这些目标，我们将使用跨学科的 结合有机化学、多肽合成和广泛应用的方法 药理学特征。强效亲脂类似物(H-Tyr-D-Ala- Phe-Phe-NH2)和极性原型类似物(Tyr-D-Arg-Phe-Lys-NH2)，都是 表现出较高的Mu受体选择性，将作为先导化合物 分别开发具有高亲油性或极性的类似物。 拟议的多肽类似物的设计将包括取代 非同寻常的氨基酸、多肽键修饰和构象 受限(循环)类比。的受体亲和力和选择性 新的类似物将在基于位移的结合分析中确定 来自大鼠脑或豚鼠的Mu、Delta和Kappa选择性放射性配体 猪脑膜结合部位。新的阿片类激动剂的活性 化合物将在体外进行基于抑制作用的生物检测 电诱发豚鼠回肠和血管收缩 小鼠、大鼠、仓鼠和兔子的生育障碍。相对稳定性 抗酶降解的类似物(大鼠脑肽酶)将 接受检查。这些化合物的止痛活性将在#年进行测定。 小鼠扭动试验，一种允许检测到 外周抗伤害性，并在小鼠热板试验中检测到 只有中枢作用的阿片类药物。外周调节的发生 止痛效果将通过季胺类阿片类药物来证实。 对抗者。阿片肽的胎盘移植与胎儿效应 类似物将使用慢性受孕的孕妇来确定 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.