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

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 MT1-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 MT1 ligand with an 11-fold preference over MT2 receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT1 receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers.