Pliska V, Heiniger J
Institute of Animal Science, Swiss Federal Institute of Technology, ETH Zurich.
Int J Pept Protein Res. 1988 Jun;31(6):520-36. doi: 10.1111/j.1399-3011.1988.tb00911.x.
Published and newly calculated pA2-values of 147 neurohypophyseal hormone analogues (7 positions varied) acting as inhibitors of oxytocin on isolated rat uterus in vitro have been subjected to fractionation according to the method by Free and Wilson which was slightly modified for this purpose. The computation was carried out in several steps. After each step, substances with outlying pA2-values were eliminated. The reduced group containing 73-79% of the original substances displayed a high degree of additivity of side chain contributions (SCC). This group seems to follow the "participation" rule as formulated by Free and Wilson. Analysis of the group of eliminated substances and of the resulting SCC-spectrum (level diagram) enabled us to draw some conclusions concerning the structural requirements of receptor binding: i) The intact ring structure is necessary for the peptide-receptor interaction: linear peptides or peptides with an extended ring are always outliers; ii) Carba analogues (substitution with CH2 in the disulfide ring) display better affinities than peptides with an S-S ring; D-Arg8 substitution decreases the binding affinity; iii) Considerably better additivity is achieved when peptides are divided into subgroups with vasopressin-like and oxytocin-like features; populations of receptors more specific for vasopressin and for oxytocin, respectively, can be assumed. Estimates of the "true" receptor-peptide dissociation constants can be obtained by summation of the corresponding SCC's in each investigated position. The value obtained for oxytocin is identical with the medium affinity binding site on myometrial cells, and not with the high affinity site. A nonlinear relationship exists between SCC's computed from pA2-values for magnesium-free and magnesium-containing (0.5 mM) media but no evidence speaks in favor of a Mg-potentiating effect on receptor binding.
已发表的以及新计算出的147种神经垂体激素类似物（7个位置可变）作为催产素对离体大鼠子宫的体外抑制剂的pA2值，已根据弗里和威尔逊的方法进行了分级分离，为此对该方法进行了轻微修改。计算分几步进行。每一步之后，去除pA2值异常的物质。包含原始物质73 - 79%的简化组显示出侧链贡献（SCC）的高度加和性。该组似乎遵循弗里和威尔逊提出的“参与”规则。对去除物质组和所得SCC谱（能级图）的分析使我们能够就受体结合的结构要求得出一些结论：i）完整的环结构对于肽 - 受体相互作用是必要的：线性肽或环扩展的肽总是异常值；ii）碳环类似物（二硫键环中用CH2取代）比具有S - S环的肽表现出更好的亲和力；D - Arg8取代降低结合亲和力；iii）当将肽分为具有加压素样和催产素样特征的亚组时，可实现明显更好的加和性；可以假定分别对加压素和催产素更具特异性的受体群体。通过对每个研究位置的相应SCC求和，可以获得“真实”受体 - 肽解离常数的估计值。催产素得到的值与子宫肌层细胞上的中等亲和力结合位点相同，而不是与高亲和力位点相同。在无镁和含镁（0.5 mM）培养基中由pA2值计算出的SCC之间存在非线性关系，但没有证据支持镁对受体结合有增强作用。
