Lin M, Chan M F, Balaji V N, Castillo R S, Larive C K
Department of Chemistry, University of Kansas, Lawrence, USA.
Int J Pept Protein Res. 1996 Sep;48(3):229-39. doi: 10.1111/j.1399-3011.1996.tb00836.x.
Two endothelin antagonists cyclo(D-Leu-D-Val-Pro-D-Asp-Trp) (IPI-147), and cyclo (D-Trp-D-Asp-Ac3c-D-Val-Leu) (IPI-725) have been synthetized. Their solution conformations have been studied in aqueous solution by NMR spectroscopy and dynamics simulation. Activity studies show that IPI-725 is a strong ETA antagonist, while IPI-147 is a weak ETA antagonist. Comparison of the solution conformations of these two ETA antagonists suggests that the difference in their activities results from their structural differences. IPI-147 contains a type II beta-turn with a hydrogen bond between NH of D-Val and the C = O of D-Asp. IPI-725, on the other hand, contains two turns, a type II beta-turn with a hydrogen bond between NH of D-Asp and C = O of D-Val, as well as a gamma'-turn with a hydrogen bond formed between D-Val NH and D-Asp carbonyl group. Therefore IPI-147 appears to be more flexible than IPI-725. Although both beta-turns contain the same residues, their orders in the turn are reversed. The beta-turn in IPI-725 is formed with D-Val:Leu:D-Trp:D-Asp, while in IPI-147, the beta-turn is formed with D-Asp:Trp:D-Leu:D-Val. The activities and solution conformations of IPI-147 and IPI-725 were also compared with BQ-123 [cyclo(D-Trp-D-Asp-Pro-D-Val-Leu)], a well characterized, highly potent endothelin antagonist.
已合成了两种内皮素拮抗剂环（D-亮氨酸-D-缬氨酸-脯氨酸-D-天冬氨酸-色氨酸）（IPI-147）和环（D-色氨酸-D-天冬氨酸-Ac3c-D-缬氨酸-亮氨酸）（IPI-725）。通过核磁共振光谱和动力学模拟研究了它们在水溶液中的溶液构象。活性研究表明，IPI-725是一种强效的ETA拮抗剂，而IPI-147是一种弱ETA拮抗剂。比较这两种ETA拮抗剂的溶液构象表明，它们活性的差异源于其结构差异。IPI-147含有一个II型β-转角，在D-缬氨酸的NH与D-天冬氨酸的C=O之间存在氢键。另一方面，IPI-725含有两个转角，一个II型β-转角，在D-天冬氨酸的NH与D-缬氨酸的C=O之间存在氢键，以及一个γ'-转角，在D-缬氨酸NH与D-天冬氨酸羰基之间形成氢键。因此，IPI-147似乎比IPI-725更具柔性。尽管两个β-转角都包含相同的残基，但它们在转角中的顺序相反。IPI-725中的β-转角由D-缬氨酸：亮氨酸：D-色氨酸：D-天冬氨酸形成，而在IPI-147中，β-转角由D-天冬氨酸：色氨酸：D-亮氨酸：D-缬氨酸形成。还将IPI-147和IPI-725的活性和溶液构象与BQ-123[环（D-色氨酸-D-天冬氨酸-脯氨酸-D-缬氨酸-亮氨酸）]进行了比较，BQ-123是一种特征明确、高效的内皮素拮抗剂。
