title: Analysis of structure-activity relationships for MT2 selective antagonists by melatonin MT1 and MT2 receptor models.
abstract: Three-dimensional homology models of human MT(1) and MT(2) melatonin receptors were built with the aim to investigate the structure-activity relationships (SARs) of MT(2) selective antagonists. A common interaction pattern was proposed for a series of structurally different MT(2) selective antagonists, which were positioned within the binding site by docking and simulated annealing. The proposed antagonist binding mode to the MT(2) receptor is characterized by the accommodation of the out-of-plane substituents in a hydrophobic pocket, which resulted as being fundamental for the explanation of the antagonist behavior and the MT(2) receptor selectivity. Moreover, to assess the ability of the MT(2) receptor model to reproduce the SARs of MT(2) antagonists, three new derivatives of the MT(2) selective antagonist N-[1-(4-chloro-benzyl)-4-methoxy-1H-indol-2-ylmethyl]-propionamide (7) were synthesized and tested for their receptor affinity and intrinsic activity. These compounds were docked into the MT(2) receptor model and were submitted to molecular dynamics studies, providing results in qualitative agreement with the experimental data. These results confirm the importance of the out-of-plane group in receptor binding and selectivity and provide a partial validation of the proposed G protein-coupled receptor model.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, Italy. silvia.rivara@unipr.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Simone
authors.initials: S
authors.lastname: Lorenzi
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D044122:Receptor, Melatonin, MT1 / Q000737:chemistry* / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D007211:Indoles; C501757:N-(1-(4-chlorobenzyl)-4-methoxy-1H-indol-2-ylmethyl)propionamide; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2