Synthesis and Functional Characterization of Substituted Isoquinolinones as MT(2)-Selective Melatoninergic Ligands

A series of substituted isoquinolinones were synthesized and their binding affinities and functional activities towards human melatonin MT(1) and MT(2) receptors were evaluated. Structure-activity relationship analysis revealed that substituted isoquinolinones bearing a 3-methoxybenzyloxyl group at C5, C6 or C7 position respectively (C5>C6>C7 in terms of their potency) conferred effective binding and selectivity toward the MT(2) receptor, with 15b as the most potent compound. Most of the tested compounds were MT(2)-selective agonists as revealed in receptor-mediated cAMP inhibition, intracellular Ca(2+) mobilization and phosphorylation of extracellular signal-regulated protein kinases. Intriguingly, compounds 7e and 7f bearing a 4-methoxybenzyloxyl group or 4-methylbenzyloxyl at C6 behaved as weak MT(2)-selective antagonists. These results suggest that substituted isoquinolinones represent a novel family of MT(2)-selective melatonin ligands. The position of the substituted benzyloxyl group, and the substituents on the benzyl ring appeared to dictate the functional characteristics of these compounds.