Mapping the melatonin receptor. 7. Subtype selective ligands based on beta-substituted N-acyl-5-methoxytryptamines and beta-substituted N-acyl-5-methoxy-1-methyltryptamines.
A series of beta-substituted and beta,beta-disubstituted N-acyl 5-methoxy-1-methyltryptamines and 5-methoxytryptamines have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human MT(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency of all analogues was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. beta-Methylmelatonin (17a) and beta,beta-dimethylmelatonin (17b), though showing a slight decrease in binding at human receptors, show an increase in potency on Xenopus. N-Butanoyl 5-methoxy-1-methyl-beta,beta-trimethylenetryptamine (12c) is an antagonist at human MT(1) receptors but an agonist at MT(2), while N-butanoyl 5-methoxy-1-methyl-beta,beta-tetramethylenetryptamine (13c) is an antagonist at MT(1) but had no action at MT(2) and is one of the first examples of an MT(1) selective antagonist.
Tsotinis
Andrew
A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Panepistimioupoli-Zografou, Athens 157 71, Greece. tsotinis@pharm.uoa.gr
Vlachou
Margarita
M
Papahatjis
Demetris P
DP
Calogeropoulou
Theodora
T
Nikas
Spyros P
SP
Garratt
Peter J
PJ
Piccio
Vincent
V
Vonhoff
Stefan
S
Davidson
Kathryn
K
Teh
Muy-Teck
MT
Sugden
David
D
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008547:Melanophores / Q000187:drug effects / Q000378:metabolism; D008550:Melatonin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D010860:Pigments, Biological / Q000096:biosynthesis; D011869:Radioligand Assay; D044122:Receptor, Melatonin, MT1 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis* / Q000494:pharmacology; D014982:Xenopus laevis
D008024:Ligands; D010860:Pigments, Biological; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011994:Recombinant Proteins; D014363:Tryptamines; D008550:Melatonin