褪黑素
兴奋剂
吲哚试验
褪黑激素受体
化学
立体化学
受体
生物活性
部分激动剂
药理学
生物
生物化学
内分泌学
体外
作者
Andrew Tsotinis,Pandelis A. Afroudakis,Peter J. Garratt,Alina Bocianowska‐Zbrog,David Sugden
出处
期刊:ChemMedChem
[Wiley]
日期:2014-07-08
卷期号:9 (10): 2238-2243
被引量:13
标识
DOI:10.1002/cmdc.201402122
摘要
Abstract Two series of analogues were designed, synthesised and evaluated as potential human melatonin type 1 and 2 receptor (hMT 1 and hMT 2 ) ligands. Their biological effects were assessed by a well‐established, specific model of melatonin action, the pigment response of Xenopus laevis melanophores. Compounds containing a benzocyclobutane scaffold and a methoxy group in the “melatonin” orientation were found to be potent agonists, with one of the analogues exhibiting activity comparable to melatonin. In contrast, analogues with a methoxy group in non‐melatonin positions or with multiple methoxy groups showed either weaker agonist activity or were antagonists. Benzocycloheptene derivatives with one methoxy group are found to be weak agonists, whereas those with two methoxy groups were found to be antagonists, as were all of the benzocycloheptane derivatives evaluated. The most active compounds were assessed in a human receptor radio ligand binding assay but showed little discrimination between MT 1 and MT 2 . These results again show that the indole nitrogen of melatonin is not a necessary component for analogue activity and also illustrate that replacement of the indole ring with a 4‐membered carbocycle can provide highly active compounds when the methoxy group is in the melatonin position.
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