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

FMRF-NH2 的合成类似物

• 批准号: 3213198
• 负责人: KEVIN BURGESS
• 金额: $ 11.01万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213198
• 关键词: X ray crystallography; aminoacid; chemical structure function; computer assisted sequence analysis; inhibitor /antagonist; laboratory rat; molecular dynamics; neuropeptides; neuropharmacologic agent; neuropharmacology; neurotransmitters; nuclear magnetic resonance spectroscopy; opioid receptor; peptide analog; peptide chemical synthesis; proline; protein sequence; synthetic peptide

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.

神经调节剂的环丙基氨基酸类似物（cyclopropylogs） 制备肽FMRF-NH 2和F-8-F-NH 2。 关于这些的文献 这些物质表明它们的活性取决于ArgPheNH 2 C-末端 所以初期的工作将集中在这个片段上。 所有四 将合成并掺入Phe的非对映体环丙基log 进入FMRF-NH 2的Phe 4位置和进入F-8-F-NH 2的Phe 8位置。 这八种肽将用于吗啡激动剂和拮抗剂的测试 活动 我们还将制备以下四种非对映体的环丙基log化合物： Arg，将它们掺入FMRF-NH 2和F-8-F-NH 2中，并测试这些 peptidomimetics以同样的方式。 非对映体环丙基log的 还将制备这两种肽的其它氨基酸组分 并取代它们的母体残基。 共48单 替代品是可能的，比可以准备和测试在 在所要求的预算范围内， 将被放置在关键的ArgPheNH 2残基附近的取代上。 肽模拟物的分离分子的构象偏好 (and它们的母体肽）将通过NMR评估，并且这些结果将 与使用QUANTA-CHARMm进行的计算相关。 在可能的情况下， 肽模拟物的固态结构将使用 X射线晶体学 这些数据将提供形状的指示， 参与这些分子识别的受体表面 神经调节肽，为计算机辅助设计奠定基础 和合成可以结合到 被认为是阿片拮抗剂受体表面。 从长远来看， 与人脑中适当的受体表面相互作用， 不刺激它（即不是阿片拮抗剂）可用于预防 对镇痛药的耐受性和依赖性。 其他化合物，人造F-8-F- NH 2相关拮抗剂，可以开发以减轻不希望的 吗啡及相关物质戒断的影响。