Novel conformationally constrained analogues of agomelatine as new melatoninergic ligands

• Published in: Molecules (Basel, Switzerland) Vol. 18; no. 1; pp. 154 - 166
• Main Authors: Rami, Marouan, Landagaray, Elodie, Ettaoussi, Mohamed, Boukhalfa, Koussayla, Caignard, Daniel-Henri, Delagrange, Philippe, Berthelot, Pascal, Yous, Saïd
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 24.12.2012; MDPI AG
• Subjects: Acetamides - chemistry; agomelatine; agonist; Animals; CHO Cells; conformationally restriction; Cricetinae; Isoxazoles - metabolism; Ligands; melatonin; Oxazolidinones - metabolism; Pyrrolidinones - metabolism; Radioligand Assay; Receptor, Melatonin, MT1 - metabolism; Receptor, Melatonin, MT2 - metabolism; Structure-Activity Relationship; Tetrazoles - metabolism; Thiazoles - metabolism
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules18010154

Novel conformationally restricted analogues of agomelatine were synthesized and pharmacologically evaluated at MT₁ and MT₂ melatoninergic receptors. Replacement of the N-acetyl side chain of agomelatine by oxathiadiazole-2-oxide (compound 3), oxadiazole-5(4H)-one (compound 4), tetrazole (compound 5), oxazolidinone (compound 7a), pyrrolidinone (compound 7b), imidazolidinedione (compound 12), thiazole (compounds 13 and 14) and isoxazole moieties (compound 15) led to a decrease of the melatoninergic binding affinities, particularly at MT₁. Compounds 7a and 7b exhibiting nanomolar affinity towards the MT₂ receptors subtypes have shown the most interesting pharmacological results of this series with the appearance of a weak MT₂-selectivity.