Hruby V J, Mosberg H I
Peptides. 1982 May-Jun;3(3):329-36. doi: 10.1016/0196-9781(82)90095-x.
Most small peptide hormones and neurotransmitters are highly flexible, conformationally labile molecules in aqueous and other environments. Thus efforts to determine the relationships between conformational properties of these peptides in aqueous and other solvents and their biological activities at membrane receptors have been difficult and of limited success. One approach which may provide a more rational basis for conformation-activity relationships is the design of conformationally restricted, semi-rigid analogs of the native peptides which still possess high potency and/or antagonist properties. In addition to the increased likelihood that the conformational properties determined for these derivatives in aqueous or other solvent environments will have biological relevance, such analogs are likely to have higher specificity for particular receptors, greater in vivo stability, and perhaps even oral activity. The application of this approach to the design of highly potent oxytocin antagonists is discussed with particular emphasis on the conformational and dynamic properties which appear to differentiate agonist and antagonist analogs. The results of these studies are briefly compared with similar studies with somatostatin, angiotensin, bradykinin, alpha-melanotropin and enkephalin, and discussed in terms of likely further developments.
大多数小肽激素和神经递质在水性和其他环境中都是高度灵活、构象不稳定的分子。因此，确定这些肽在水性和其他溶剂中的构象性质与其在膜受体上的生物活性之间的关系一直很困难，且成效有限。一种可能为构效关系提供更合理基础的方法是设计构象受限的、半刚性的天然肽类似物，这些类似物仍具有高效能和/或拮抗特性。除了在水性或其他溶剂环境中测定的这些衍生物的构象性质更有可能具有生物学相关性外，此类类似物可能对特定受体具有更高的特异性、更高的体内稳定性，甚至可能具有口服活性。本文讨论了这种方法在设计高效能催产素拮抗剂中的应用，特别强调了似乎能区分激动剂和拮抗剂类似物的构象和动态性质。这些研究结果与对生长抑素、血管紧张素、缓激肽、α-促黑素和脑啡肽的类似研究进行了简要比较，并就可能的进一步发展进行了讨论。
