Goodman M, Ro S, Yamazaki T, Spencer J R, Toy A, Huang Z, He Y, Reisine T
Department of Chemistry, University of California, San Diego, La Jolla.
Bioorg Khim. 1992 Oct-Nov;18(10-11):1375-93.
For the studies of bioactive peptides, our laboratories have been employed an integrated approach including synthesis, bioassays, and conformational analysis. To obtain highly potent, selective and metabolically stable analogs, peptidomimetics such as peptide backbone modifications (retro-inverso structures), constrained amino acids, and cyclic structures have been incorporated into many bioactive peptide sequences. The conformational studies of the resulting analogs have led to topochemical models for the bioactivities of those peptides. This lecture will be focused on the results of such studies on opioids and somatostatin. We have synthesized numerous opioid analogs with various peptidomimetics based on three classes: enkephalins, dermorphin-deltorphins, and morphiceptins. Many of these analogs exhibit high potency, selectivity, and metabolic stability. Conformational studies of these analogs have enabled us to define the structural characteristics necessary for bioactivities of morphiceptins, dermorphins, enkephalins, and deltorphins. From these results, we can propose conformational models responsible for bioactivities at the mu- and delta-receptors. Our studies of cyclic somatostatin analogs are based on the highly active Merck analog c(-Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11-) (where the superscripts denote position in native somatostatin). To investigate the topochemical preference of backbone and side chains, unusual amino acids, including beta-methylphenylalanine7 or 11, beta-methyltryptophan8, as well as backbone modifications such as retro-inverso structures have been incorporated. The bioactivity profiles of these peptidomimetic molecules provide much information on the effects of backbone and side chain constraints on bioactivity.
对于生物活性肽的研究，我们实验室采用了一种综合方法，包括合成、生物测定和构象分析。为了获得高效、选择性和代谢稳定的类似物，肽模拟物如肽主链修饰（反向结构）、受限氨基酸和环状结构已被纳入许多生物活性肽序列中。对所得类似物的构象研究导致了这些肽生物活性的拓扑化学模型。本次讲座将聚焦于对阿片类药物和生长抑素的此类研究结果。我们基于三类合成了许多带有各种肽模拟物的阿片类类似物：脑啡肽、皮啡肽 - 德尔托啡肽和吗啡肽。这些类似物中的许多都表现出高效力、选择性和代谢稳定性。对这些类似物的构象研究使我们能够确定吗啡肽、皮啡肽、脑啡肽和德尔托啡肽生物活性所需的结构特征。从这些结果中，我们可以提出负责μ和δ受体生物活性的构象模型。我们对环状生长抑素类似物的研究基于高活性的默克类似物c(-Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11-)（其中上标表示在天然生长抑素中的位置）。为了研究主链和侧链的拓扑化学偏好，已纳入不寻常的氨基酸（包括β-甲基苯丙氨酸7或11、β-甲基色氨酸8）以及主链修饰（如反向结构）。这些肽模拟分子的生物活性谱提供了许多关于主链和侧链限制对生物活性影响的信息。
