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A series of substituted isoquinolinones were synthesized and their binding affinities and functional activities towards human melatonin MT1 and MT2 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 MT2 receptor, with 15b as the most potent compound. Most of the tested compounds were MT2-selective agonists as revealed in receptor-mediated cAMP inhibition, intracellular Ca2+ 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 MT2-selective antagonists. These results suggest that substituted isoquinolinones represent a novel family of MT2-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.

A series of novel and selective N-[3-(6-benzyloxy-3-methoxyphenyl)propyl] amides has recently been shown to possess sub-nanomolar range binding affinity to the type 2 melatonin receptor (MT(2)). Pharmacokinetics studies suggested that these compounds were subject to vigorous CYP450-mediated metabolism, resulting in a series of metabolites with significantly decreased or diminished binding affinities toward MT(2) receptor. The ether bonds were found to be the major positions susceptible to metabolism. In this study, the benzyl ether bond was either removed or replaced with a carbon-carbon bond in an attempt to improve metabolic stability and enhance their resistance towards phase I oxidation. The synthesis, receptor binding affinity, intrinsic potency and metabolic stability of modified structures are reported in this article. By removal or replacement of metabolic labile ether linkerage with carbon linkers, a novel compound was identified with good potency and MT(2) selectivity, and with increased metabolic stability., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Melatonin is a widely distributed hormone that regulates several major physiological processes, including the circadian rhythm and seasonal adaptation. The two subtypes of mammalian G protein-coupled melatonin receptors are primarily responsible for mediating the actions of melatonin. Because synthetic melatonin agonists have considerable therapeutic potentials in modulating insomnia and circadian- related sleep disorders, it is highly desirable to develop subtype-selective melatoninergic compounds. The pharmacological potencies of a series of substituted N-[3-(3-methoxyphenyl)propyl] amides towards human melatonin MT(1) and MT(2) receptors were evaluated by the FLIPR high-throughput screening assay, whilst their subtype-selectivity was subsequently verified with ERK phosphorylation and cAMP assays. Structure-activity relationship analysis of highly potent subtype-selective ligands (MT(2) EC(50) 10-90 pM) revealed that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT(2) potency and at the same time decreased MT(1) potency. Incorporation of structural moieties conferring the subtype selectivity produced several extremely potent MT(2)-selective ligands. The most potent subtype-selective ligand, 2q had a substantially higher potency for MT(2) receptor than melatonin for elevation of [Ca(2+)]i and inhibition of forskolin-elevated cAMP. Representative MT(2)-selective ligands also induced ERK phosphorylation in both recombinant and native cell lines, and no cross-reactivity to 17 other GPCRs could be detected. These ligands represent invaluable tools for delineating the functional roles of distinct melatonin receptor subtypes and are viable candidates for drug development.

A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their binding affinities towards human melatonin MT(1) and MT(2) receptors were evaluated. It was discovered that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT(2) binding affinity and at the same time decreased MT(1) binding affinity., (Copyright 2010 Elsevier Ltd. All rights reserved.)