High affinity rigidified AT2 receptor ligands with indane scaffolds

被引:7
|
作者
Wallinder, Charlotta [1 ]
Skold, Christian [1 ]
Sundholm, Sara [1 ]
Guimond, Marie-Odile [3 ]
Yahiaoui, Samir [1 ]
Lindeberg, Gunnar [1 ]
Gallo-Payet, Nicole [3 ]
Hallberg, Mathias [2 ]
Alterman, Mathias [1 ]
机构
[1] Uppsala Univ, BMC, Dept Med Chem, POB 574, SE-75123 Uppsala, Sweden
[2] Uppsala Univ, BMC, Div Biol Res Drug Dependence, Beijer Lab,Dept Pharmaceut Biosci, POB 591, SE-75124 Uppsala, Sweden
[3] Univ Sherbrooke, Fac Med & Hlth Sci, Serv Endocrinol, Sherbrooke, PQ J1H 5N4, Canada
基金
瑞典研究理事会; 加拿大健康研究院;
关键词
2; ANGIOTENSIN-II; NEURITE OUTGROWTH; AT2; RECEPTOR; BIOLOGICAL EVALUATION; TYPE-2; NG108-15; AGONISTS; ANTAGONISTS; KINASE; AT2-RECEPTOR;
D O I
10.1039/c9md00402e
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.
引用
收藏
页码:2146 / 2160
页数:15
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