Synthesis and structure-affinity-activity relationships of novel benzofuran derivatives as MT2 melatonin receptor selective ligands

A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the two MT1 and MT2 melatonin receptor subtypes was determined by binding studies using 2-[I-125] iodomelatonin on human embryonic kidney cell line HEK293 membrane homogenates. The intrinsic activity of the most interesting compounds was evaluated on the [S-35] GTPgammaS binding assay. Introduction of a 2-phenyl substituent in the C-2 benzofuran position leads to an agonist compound, 10q, which binds more strongly than melatonin itself to both MT1 and MT2 subtypes. On the other hand, a 2-benzyl group in the same position allows MT2 antagonist selective ligands to be obtained. The MT2 selectivity and antagonist potency can be modulated with suitable modifications on the N-acyl and benzyl substituents, and the most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively, and bind to the MT2 subtype similarly to melatonin itself (0.1 nM). Nevertheless, 10c acts as an MT1 and MT2 antagonist, whereas 19 is a partial agonist.