7-Substituted-melatonin and 7-substituted-1-methylmelatonin analogues: Effect of substituents on potency and binding affinity

A series of 7-substituted melatonin and 1-methylmelatonin analogues were prepared and tested against human and amphibian melatonin receptors. 7-Substituents reduced the agonist potency of all the analogues in the Xenopus laevis melanophore assay, 7-bromomelatonin ( 5d) and N-butanoyl 7-bromo-5-metho...

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Published in:Bioorganic & medicinal chemistry 2007-07, Vol.15 (13), p.4543-4551
Main Authors: Faust, Rüdiger, Garratt, Peter J., Trujillo Pérez, Maria Angeles, Piccio, Vincent J.-D., Madsen, Christian, Stenstrøm, Ane, Frølund, Bente, Davidson, Kathryn, Teh, Muy-Teck, Sugden, David
Format: Article
Language:English
Subjects:
Animals
Antioxidants - chemical synthesis
Antioxidants - metabolism
Antioxidants - pharmacology
Biological and medical sciences
Cell Line
Human melatonin receptors
Humans
Medical sciences
Melanophores
Melatonin
Melatonin - analogs & derivatives
Melatonin - chemical synthesis
Melatonin - pharmacology
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Receptor, Melatonin, MT1 - drug effects
Receptor, Melatonin, MT1 - metabolism
Receptor, Melatonin, MT2 - drug effects
Receptor, Melatonin, MT2 - metabolism
Recombinant Proteins - metabolism
Structure-Activity Relationship
Suzuki coupling reaction
Xenopus laevis
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Summary:A series of 7-substituted melatonin and 1-methylmelatonin analogues were prepared and tested against human and amphibian melatonin receptors. 7-Substituents reduced the agonist potency of all the analogues in the Xenopus laevis melanophore assay, 7-bromomelatonin ( 5d) and N-butanoyl 7-bromo-5-methoxytryptamine ( 5f) being the most active compounds, but both were 42-fold less potent than melatonin ( 1). Whereas all the analogues bind with lower affinity at the human MT 1 receptor than melatonin, 5d, 5f and N-propanoyl 7-bromo-5-methoxytryptamine ( 5e) show a similar binding affinity to melatonin at the MT 2 receptor and consequently show some MT 2 selectivity. These results suggest that the receptor pocket around C-7 favours binding by an electronegative group, suggesting an electropositive region in this area of the receptor.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.04.013