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-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.
Faust
Rüdiger
R
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
Garratt
Peter J
PJ
Trujillo Pérez
Maria Angeles
MA
Piccio
Vincent J-D
VJ
Madsen
Christian
C
Stenstrøm
Ane
A
Frølund
Bente
B
Davidson
Kathryn
K
Teh
Muy-Teck
MT
Sugden
David
D
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D044122:Receptor, Melatonin, MT1 / Q000187:drug effects / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000975:Antioxidants; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011994:Recombinant Proteins; D008550:Melatonin