Johannesson Petra, Erdélyi Máté, Lindeberg Gunnar, Frändberg Per-Anders, Nyberg Fred, Karlén Anders, Hallberg Anders
Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
J Med Chem. 2004 Nov 18;47(24):6009-19. doi: 10.1021/jm049651m.
This paper reports the synthesis of two angiotensin II analogues with tyrosine-functionalized 5,5-bicyclic thiazabicycloalkane dipeptide mimetics replacing the Tyr(4)-Ile(5) residues. The preparation of these analogues relies on the synthesis and incorporation of an alpha,alpha-disubstituted chimeric amino acid derivative and on-resin bicyclization to a cysteine residue. The synthesized analogues both displayed high angiotensin AT(2)/AT(1) receptor binding preferences and had AT(2) receptor affinities in the same low nanomolar range as angiotensin II itself. Conformational analysis, using experimental constraints derived from NMR studies, indicated that the Tyr(4) and His(6) residues in one of the angiotensin II analogues were in close proximity to each other.
本文报道了两种血管紧张素II类似物的合成，其酪氨酸功能化的5,5-双环噻唑并双环烷二肽模拟物取代了Tyr(4)-Ile(5)残基。这些类似物的制备依赖于α,α-二取代嵌合氨基酸衍生物的合成与掺入以及与半胱氨酸残基的树脂上双环化。合成的类似物均表现出对血管紧张素AT(2)/AT(1)受体的高结合偏好，且对AT(2)受体的亲和力与血管紧张素II本身处于相同的低纳摩尔范围。利用源自核磁共振研究的实验约束进行的构象分析表明，其中一种血管紧张素II类似物中的Tyr(4)和His(6)残基彼此靠近。
