title: Bivalent ligand approach on N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide: synthesis, binding affinity and intrinsic activity for MT(1) and MT(2) melatonin receptors.
abstract: We report the synthesis, binding properties and intrinsic activity at MT(1) and MT(2) melatonin receptors of new dimeric melatonin receptor ligands in which two units of the monomeric agonist N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (1) are linked together through different anchor points. Dimerization of compound 1 through the methoxy substituent leads to a substantial improvement in selectivity for the MT(1) receptor, and to a partial agonist behavior. Compound 3a, with a trimethylene linker, was the most selective for the MT(1) subtype (112-fold selectivity) and compound 3d, characterized by a hexamethylene spacer, had the highest MT(1) binding affinity (pK(iMT1)=8.47) and 54-fold MT(1)-selectivity. Dimerization through the aniline nitrogen of 1 abolished MT(1) selectivity, leading to compounds with either a full agonist or an antagonist behavior depending on the nature of the linker.
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino Carlo Bo, Piazza Rinascimento 6, 61029 Urbino, Italy. gilberto.spadoni@uniurb.it
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Orlando
authors.forename: Simone
authors.initials: S
authors.lastname: Lucarini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucini
authors.forename: Marilou
authors.initials: M
authors.lastname: Pannacci
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaglione
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019281:Dimerization; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D051381:Rats; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D008024:Ligands; D044094:Receptors, Melatonin