title: 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.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Panepistimioupoli-Zografou, Athens 157 71, Greece. tsotinis@pharm.uoa.gr
authors.forename: Andrew
authors.initials: A
authors.lastname: Tsotinis
authors.forename: Margarita
authors.initials: M
authors.lastname: Vlachou
authors.forename: Demetris P
authors.initials: DP
authors.lastname: Papahatjis
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Garratt
authors.forename: Vincent
authors.initials: V
authors.lastname: Piccio
authors.forename: Stefan
authors.initials: S
authors.lastname: Vonhoff
authors.forename: Kathryn
authors.initials: K
authors.lastname: Davidson
authors.forename: Muy-Teck
authors.initials: MT
authors.lastname: Teh
authors.forename: David
authors.initials: D
authors.lastname: Sugden
mesh_terms: 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
chemical_list: D008024:Ligands; D010860:Pigments, Biological; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011994:Recombinant Proteins; D014363:Tryptamines; D008550:Melatonin