title: N-(Anilinoethyl)amides: design and synthesis of metabolically stable, selective melatonin receptor ligands.
abstract: The class of N-(anilinoethyl)amides includes melatonin receptor ligands with varied subtype selectivity and intrinsic activity. One of these ligands, the MT(2)-selective partial agonist UCM765 (N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide), had evidenced hypnotic effects in rodents at doses > or =40 mg kg(-1) (s.c.), in spite of its sub-nanomolar affinity for human melatonin receptors. Supposing that its low in vivo potency could be due, at least in part, to metabolic liability in rat liver, UCM765 was incubated with rat liver S9 fraction and rat, mouse, or human microsomes, and the major metabolites were identified by LC-MS, synthesized, and in vitro tested for their affinity toward MT(1) and MT(2) receptors. The obtained information was exploited to design novel analogues of UCM765 that are more resistant to in vitro oxidative degradation, while maintaining a similar binding profile. The analogue UCM924 (N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide) displayed a binding profile similar to that of UCM765 on cloned human receptors (MT(2)-selective partial agonist) and a significantly longer half-life in the presence of rat liver S9 fraction.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G.P. Usberti 27A, Campus Universitario, 43124 Parma (Italy), Fax: (+39) 0521-905006.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fioni
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Caterina
authors.initials: C
authors.lastname: Carmi
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucini
authors.forename: Marilou
authors.initials: M
authors.lastname: Pannacci
authors.forename: Alessia
authors.initials: A
authors.lastname: Caronno
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaglione
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
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
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D002458:Cell Fractionation; D015195:Drug Design; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D008024:Ligands; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044122:Receptor, Melatonin, MT1 / Q000819:agonists*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists*
chemical_list: D000081:Acetamides; D000814:Aniline Compounds; D006993:Hypnotics and Sedatives; D008024:Ligands; C545681:N-(2-((3-bromophenyl)-(4-fluorophenyl)amino)ethyl)acetamide; C545680:N-(2-((3-methoxyphenyl)phenylamino)ethyl)acetamide; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2