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N ‐(Anilinoethyl)amides: Design and Synthesis of Metabolically Stable, Selective Melatonin Receptor Ligands
Author(s) -
Rivara Silvia,
Vacondio Federica,
Fioni Alessandro,
Silva Claudia,
Carmi Caterina,
Mor Marco,
Lucini Valeria,
Pannacci Marilou,
Caronno Alessia,
Scaglione Francesco,
Gobbi Gabriella,
Spadoni Gilberto,
Bedini Annalida,
Orlando Pierfrancesco,
Lucarini Simone,
Tarzia Giorgio
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900240
Subject(s) - acetamide , partial agonist , receptor , agonist , microsome , in vivo , intrinsic activity , melatonin , in vitro , chemistry , s9 fraction , melatonin receptor , potency , biochemistry , pharmacology , stereochemistry , biology , endocrinology , microbiology and biotechnology , organic chemistry
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 ≥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.