Haskell-Luevano C, Toth K, Boteju L, Job C, Castrucci A M, Hadley M E, Hruby V J
Department of Chemistry, University of Arizona, Tucson 85721, USA.
J Med Chem. 1997 Aug 15;40(17):2740-9. doi: 10.1021/jm970018t.
Topographically modified melanotropin side chain pharmacophore residues Phe7 and Trp9 in a cyclic peptide template (Ac-Nle4-c[Asp-His-Xaa7-Arg-Yaa9-Lys]-NH2) and Phe7 in a linear peptide template (Ac-Ser-Tyr-Ser-Nle4-Glu-His-Xaa7-Arg-Trp-Gly-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of beta-methylphenylalanine (beta-MePhe)7 and beta-methyltryptophan (beta-MeTrp)9 and the two isomers of 1,2,3,4-tetrahydro-beta-carboline (Tca)9 Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the beta-MePhe7 stereoisomeric peptides; up to a 476-fold difference in potency resulted for the beta-MeTrp9 peptides, and about a 50-fold difference between the Tca9-containing peptides. Up to a 40-fold difference in potency resulted for the beta-MePhe7 stereoisomeric peptides using the linear template in these assays. The relative potency ranking for modifications in the cyclic template of beta-MePhe7 were 2R,3S > 2S,3S = 2S,3R > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of beta-MeTrp9 were 2R,3S > 2R,3R > 2S,3S > > 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca9 were DTca > LTca in both assays. Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the beta-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of beta-MeTrp9 stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.
在环状肽模板（Ac-Nle4-c[Asp-His-Xaa7-Arg-Yaa9-Lys]-NH2）中，经拓扑结构修饰的促黑素侧链药效团残基苯丙氨酸7（Phe7）和色氨酸9（Trp9），以及线性肽模板（Ac-Ser-Tyr-Ser-Nle4-Glu-His-Xaa7-Arg-Trp-Gly-Lys-Pro-Val-NH2）中的Phe7，在青蛙和蜥蜴皮肤生物测定中导致了效力差异和生物活性的延长。这些拓扑修饰包括β-甲基苯丙氨酸（β-MePhe）7和β-甲基色氨酸（β-MeTrp）9的四种异构体，以及1,2,3,4-四氢-β-咔啉（Tca）9的两种异构体。环状模板中的修饰导致β-MePhe7立体异构肽的效力差异高达1000倍；β-MeTrp9肽的效力差异高达476倍，含Tca9的肽之间的差异约为50倍。在这些测定中，使用线性模板的β-MePhe7立体异构肽的效力差异高达40倍。在青蛙测定中，β-MePhe7环状模板修饰的相对效力排名为2R,3S > 2S,3S = 2S,3R > 2R,3R，在蜥蜴测定中为2S,3R > 2R,3S > 2S,3S > 2R,3R。β-MeTrp9环状模板修饰的相对效力在青蛙测定中为2R,3S > 2R,3R > 2S,3S > > 2S,3R，在蜥蜴测定中为2S,3S = 2R,3R > 2R,3S > 2S,3R。Tca9环状模板修饰的相对效力在两种测定中均为DTca > LTca。还观察到这些修饰肽在延长（残留）活性方面存在显著差异，这取决于β-甲基氨基酸的立体化学、肽模板和生物测定系统。此外，对青蛙、蜥蜴和人类MC1受体上的β-MeTrp9立体异构肽的比较表明，经典青蛙和蜥蜴皮肤生物测定中的构效关系不一定能预测人类黑皮质素受体相应的构效关系图谱，这表明MC1受体需求具有显著的物种特异性。
