title: Synthesis and structure-affinity-activity relationships of novel benzofuran derivatives as MT(2) melatonin receptor selective ligands.
abstract: A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the two MT(1) and MT(2) melatonin receptor subtypes was determined by binding studies using 2-[(125)I]iodomelatonin on human embryonic kidney cell line HEK293 membrane homogenates. The intrinsic activity of the most interesting compounds was evaluated on the [(35)S]GTPgammaS binding assay. Introduction of a 2-phenyl substituent in the C-2 benzofuran position leads to an agonist compound, 10q, which binds more strongly than melatonin itself to both MT(1) and MT(2) subtypes. On the other hand, a 2-benzyl group in the same position allows MT(2) antagonist selective ligands to be obtained. The MT(2) selectivity and antagonist potency can be modulated with suitable modifications on the N-acyl and benzyl substituents, and the most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively, and bind to the MT(2) subtype similarly to melatonin itself (0.1 nM). Nevertheless, 10c acts as an MT(1) and MT(2) antagonist, whereas 19 is a partial agonist.
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Wallez
authors.forename: Sophie
authors.initials: S
authors.lastname: Durieux-Poissonnier
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Valérie
authors.initials: V
authors.lastname: Audinot
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Nicolas
authors.forename: Caroline
authors.initials: C
authors.lastname: Bennejean
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Daniel
authors.initials: D
authors.lastname: Lesieur
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008024:Ligands; D008550:Melatonin / Q000031:analogs & derivatives* / Q000378:metabolism*; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D044094:Receptors, Melatonin; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D008024:Ligands; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D008550:Melatonin