title: Binding affinity and biological activity of oxygen and sulfur isosteres at melatonin receptors as a function of their hydrogen bonding capability.
abstract: Analogues of melatonin (1) and of N-acetyl 5-ethoxytryptamine (3) in which the oxygen atoms are replaced by sulfur have been prepared and tested against human and amphibian melatonin receptors. All sulfur analogues show a decreased binding affinity at human MT1 and MT2 receptors and a reduced potency as melatonin agonists on the Xenopus melanophore assay. The 5-methoxy oxygen of melatonin is significantly more important for receptor binding than the amide oxygen. N-Acetyl 5-ethoxytryptamine shows a decrease in both binding affinity and potency in comparison with melatonin. In this series, replacing either the ethoxy or amide oxygen by sulfur has a similar but smaller effect on both binding affinity and potency. Using K(B)(H) values from Abraham's equations we have assessed the possibility of estimating EC50 values for sulfur isosteres from the EC50 values of their oxygen analogues.
authors.affiliation: Department of Chemistry, University College London, WC1H 0AJ, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Davies
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Faust
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Garratt
authors.forename: Cécile
authors.initials: C
authors.lastname: Marivingt-Mounir
authors.lastname: Kathryn Davidson
authors.forename: Muy-Teck
authors.initials: MT
authors.lastname: Teh
authors.forename: David
authors.initials: D
authors.lastname: Sugden
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D006801:Humans; D006860:Hydrogen Bonding; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013455:Sulfur / Q000737:chemistry / Q000378:metabolism*; D014363:Tryptamines / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C492868:N-acetyl-5-ethoxytryptamine; D044094:Receptors, Melatonin; D014363:Tryptamines; D013455:Sulfur; D008550:Melatonin; D010100:Oxygen