N-(Anilinoethyl)amides: design and synthesis of metabolically stable, selective melatonin receptor ligands
| Autor: | Giorgio Tarzia, Annalida Bedini, Claudia Silva, Marilou Pannacci, Alessandro Fioni, Silvia Rivara, Gilberto Spadoni, Alessia Caronno, Valeria Lucini, Pierfrancesco Orlando, Federica Vacondio, Gabriella Gobbi, Marco Mor, Caterina Carmi, Francesco Scaglione, Simone Lucarini |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Intrinsic activity Stereochemistry Biology Cell Fractionation Ligands Biochemistry Melatonin receptor Partial agonist Melatonin chemistry.chemical_compound Mice In vivo Drug Discovery Acetamides medicine Animals Humans Hypnotics and Sedatives General Pharmacology Toxicology and Pharmaceutics Rats Wistar Receptor Pharmacology Aniline Compounds Receptor Melatonin MT2 Receptor Melatonin MT1 Organic Chemistry Rats S9 fraction chemistry Drug Design Microsomes Liver Molecular Medicine Acetamide medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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