RESUMEN
Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these ligands are MT(1)-selective with nanomolar or subnanomolar affinity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes, N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide (36), a subnanomolar MT(1) ligand with an 11-fold preference over MT(2) receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT(1) receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers.
Asunto(s)
Acetamidas/farmacología , Receptores de Melatonina/antagonistas & inhibidores , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Línea Celular , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Melatonina/agonistas , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Receptor de Melatonina MT1 , Receptores de Melatonina/agonistasRESUMEN
We report the synthesis and binding properties at MT(1) and MT(2) receptors of the first example of agomelatine (N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide) dimers in which two agomelatine moieties are linked together through their methoxy substituent by a polymethylene side chain according to the "bivalent ligand" approach. Some of these compounds behave as MT(1)-selective ligands. The most selective one (5) behaves as an antagonist.