SYNTHETIC ANALOGUES OF FMRF-NH2 & F-8-F-NH

神经调节剂的环丙基氨基酸类似物(环丙基对数) 将制备FMRF-NH2和F-8-F-NH2多肽。关于这些的文献 物质表明它们的活性依赖于ArgPheNH2的C末端 因此，最初的努力将集中在这块碎片上。四个都是 将合成苯丙氨酸的非对映异构体环丙醇并与之结合 进入FMRF-NH2的Phe4位和F-8-F-NH2的Phe8位。 这八种多肽将被测试为吗啡激动剂和拮抗剂。 活动。我们还将准备四个非对映异构体环丙醇 Arg，将它们合并到FMRF-NH2和F-8-F-NH2中，并测试这些 以同样的方式模拟多肽。非对映异构体的环丙烯对数 还将制备这两种多肽的其他氨基酸成分。 并取代它们的母体残基。共有48个单人 替代是可能的，超过了在 在所要求的预算范围内，这项提案的进程，因此强调 将被放置在关键的ArgPheNH2残基附近的取代上。 多肽类药物分离分子的构象偏好 (和它们的母体多肽)将通过核磁共振进行评估，这些结果将 与使用Quanta-CHARMm进行的计算相关联。在可能的地方， 多肽模拟物的固体结构将用 X射线结晶学。这些数据将提供关于 受体表面(S)参与这些物质的分子识别 神经调节肽及其在计算机辅助设计中的应用 和合成可与之结合的分子(不一定是多肽) 著名的阿片拮抗剂受体出现。从长远来看，药物 与人脑中适当的受体表面(S)相互作用，但 不刺激它(即不是阿片类拮抗剂)可以用来防止 对止痛药的耐受性和依赖性。其他化合物，人造F-8-F- 与NH2相关的拮抗剂，可以被开发来减轻不良反应 戒断吗啡及相关物质的影响。

Cyclopropyl amino acid analogues (cyclopropylogs) of the neuromodulatory peptides FMRF-NH2 and F-8-F-NH2 will be prepared. Literature on these substances indicates that their activity depends on an ArgPheNH2 C-terminus so initial efforts will be concentrated on this fragment. All four diastereomeric cyclopropylogs of Phe will be synthesized and incorporated into the Phe4 position of FMRF-NH2 and into the Phe8 position of F-8-F-NH2. These eight peptides will be tested for morphine agonist and antagonist activity. We shall also prepare the four diastereomeric cycopropylogs of Arg, incorporate them into FMRF-NH2 and F-8-F-NH2, and test these peptidomimetics in the same way. diastereomeric cyclopropylogs of the other amino acid constituents of these two peptides will also be prepared and substituted for their parent residues. A total of 48 single substitutions are possible, more than could be prepared and tested in the course of this proposal within the budget requested, consequently emphasis will be placed on substitutions near the crucial ArgPheNH2 residue. Conformational preferences of isolated molecules of the peptidomimetics (and their parent peptides) will be assessed by NMR and these results will be correlated with calculations made using QUANTA-CHARMm. Where possible, the solid state structure of the peptidomimetics will be determined using X-ray crystallography. These data will provide indications of the shape of the receptor surface(s) involved in molecular recognition of these neuromodulatory peptides and lay foundations for computer-assisted design and synthesis of molecules (not necessarily peptides) which may bind to reputed opiate antagonist receptor surfaces. In the long term, drugs which interact with the appropriate receptor surface(s) in the human brain but do not stimulate it (i.e. are not opiate antagonists) may be used to prevent tolerance and dependance to analgesics. Other compounds, artificial F-8-F- NH2 related antagonists, could be developed to alleviate the undesirable effects of withdrawal from morphine and related substances.