Structure–Activity Relationships of 1‐Benzoylazulenes at the OX1 and OX2 Orexin Receptors
Structure–Activity Relationships of 1‐Benzoylazulenes at the OX1 and OX2 Orexin Receptors
复制标题
1-苯甲酰薁烯在 OX1 和 OX2 食欲素受体上的结构-活性关系
DOI：
10.1002/cmdc.201900074
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发表时间：
2019
期刊：
影响因子：
3.4
通讯作者：
H. Xhaard
中科院分区：
文献类型：
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作者：
Ainoleena Turku;Teppo O. Leino;Lasse Karhu;J. Yli;J. Kukkonen;Erik A. A. Wallén;H. Xhaard
我们先前证明了二或三取代的甘菊环作为食欲素受体的配体（增效剂、弱激动剂和拮抗剂）的潜力。在这项研究中，我们研究了27个1-苯甲酰基甘菊环衍生物，发现了OX 1和两个弱双重食欲素受体激动剂的食欲素反应的七个增强剂。对于增效剂，用吲哚取代甘菊环支架保留了六种化合物中四种的活性。激动作用和增强作用的构效关系可总结为被两个氢键受体（1-位，苯甲酰基; 6-位，羧基/酯）取代的双环芳环系统，彼此之间的距离为7-8个碱基; 3-位的第三个受体也耐受良好。 从分子动力学模拟中，在食欲素受体激动剂Nag 26的优选构象中发现了相同的药效特征。微妙的变化之间切换弱激动和增强活性，表明重叠的结合位点。
We previously demonstrated the potential of di‐ or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the orexin receptors. In this study we investigated 27 1‐benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX1 and two weak dual orexin receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure–activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen‐bond acceptors (1‐position, benzoyl; 6‐position, carboxyl/ester) within 7–8 Å of each other; a third acceptor at the 3‐position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the orexin receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.
影响因子：
--
作者：
James MH;Mahler SV;Moorman DE;Aston-Jones G
通讯作者：
Aston-Jones G
DOI：
10.1073/pnas.95.1.322
发表时间：
1998-01-06
影响因子：
11.1
作者：
De Lecea, L;Kilduff, TS;Sutcliffe, JG
通讯作者：
Sutcliffe, JG