SYNTHETIC CHEMISTRY AND PHARMACOLOGY

合成化学与药理学

基本信息

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
项目类别：
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

项目摘要

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.

我们建议开发新型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该是这样的：(i) 保留对 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）或硬脑膜（硬膜外给药），以及 (iii) 不能穿过胎盘屏障（PB）。预计具有这种特性的镇痛药可以通过结构修饰发现，产生物理化学性质已经发生很大变化现有的受体选择性阿片肽。作为母肽，我们将使用四种 mu 选择性阿片类四肽和二肽激动剂以及两种新型二肽δ激动剂，所有这些都是最近在 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（通过被动扩散通过）或通过增加它们携带的正电荷数量（通过非特异性、吸收性内吞作用）。预计在一定程度上亲脂性和/或一定数量和分布的正电荷可能使肽类似物能够穿过 BBB，但不能穿过 PB。亲油性将通过掺入高度疏水的人造材料来增强氨基酸进入肽和/或亲脂部分附着到端基，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新类似物的数量将在基于以下的结合测定中确定： mu、delta 和 k 选择性放射性配体从大鼠脑中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。类似物对酶促作用的相对稳定性将检查降解（大鼠脑肽酶）。镇痛活动化合物的含量将在小鼠扭体试验中测定，这是一项测试允许检测外周和中枢的模型镇静作用，并且在小鼠热板测试中仅检测到中枢介导的镇痛作用。有前途的化合物将是大规模合成用于药理学和药代动力学使用长期检测的怀孕绵羊模型进行的研究在司徒博士的实验室里。相同的化合物也将被制备氘化形式作为定量 MS 分析的标准品在Desiderio博士的实验室里。