Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT1 melatoninergic ligands

Abstract 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.