Τίτλος:
Benzocyclobutane, benzocycloheptane and heptene derivatives as melatonin agonists and antagonists
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Two series of analogues were designed, synthesised and evaluated as potential human melatonin type 1 and 2 receptor (hMT1 and hMT2) 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 MT1 and MT2. 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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Συγγραφείς:
Tsotinis, A.
Afroudakis, P.A.
Garratt, P.J.
Bocianowska-Zbrog, A.
Sugden, D.
Εκδότης:
John Wiley and Sons Ltd
Λέξεις-κλειδιά:
benzene derivative; cyclobutane derivative; cycloheptane derivative; hormone antagonist; melatonin; melatonin 1 receptor; melatonin 2 receptor; melatonin receptor agonist; melatonin; polycyclic hydrocarbon, animal cell; Article; drug design; drug effect; drug potency; drug screening; melanophore; nonhuman; receptor binding assay; Xenopus laevis; agonists; antagonists and inhibitors; proton nuclear magnetic resonance, Melatonin; Polycyclic Compounds; Proton Magnetic Resonance Spectroscopy
DOI:
10.1002/cmdc.201402122
