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Benzocyclobutane, Benzocycloheptane and Heptene Derivatives as Melatonin Agonists and Antagonists
Author(s) -
Tsotinis Andrew,
Afroudakis Pandelis A.,
Garratt Peter J.,
BocianowskaZbrog Alina,
Sugden David
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402122
Subject(s) - melatonin , agonist , indole test , melatonin receptor , chemistry , stereochemistry , receptor , biological activity , partial agonist , pharmacology , biology , biochemistry , endocrinology , in vitro
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.