N-(Anilinoethyl)amides: design and synthesis of metabolically stable, selective melatonin receptor ligands.
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.
Rivara
Silvia
S
Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G.P. Usberti 27A, Campus Universitario, 43124 Parma (Italy), Fax: (+39) 0521-905006.
Vacondio
Federica
F
Fioni
Alessandro
A
Silva
Claudia
C
Carmi
Caterina
C
Mor
Marco
M
Lucini
Valeria
V
Pannacci
Marilou
M
Caronno
Alessia
A
Scaglione
Francesco
F
Gobbi
Gabriella
G
Spadoni
Gilberto
G
Bedini
Annalida
A
Orlando
Pierfrancesco
P
Lucarini
Simone
S
Tarzia
Giorgio
G
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*
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