Melatonin is a widely distributed hormone regulating several major physiological processes, including the circadian rhythm, pubertal development and seasonal adaptation. The two subtypes of mammalian G protein-coupled receptors utilize the same panel of G proteins for signal transduction but they appear to play different functional roles. Because synthetic melatonin agonists have a high therapeutic potential in modulating insomnia and circadian-related sleep disorders, the discovery and development of subtype-selective melatoninergic compounds is highly desirable. A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their receptor binding affinities towards human melatonin MT₁ and MT₂ receptors were evaluated by radioligand binding assay. Structure-activity...[ Read more ]

Melatonin is a widely distributed hormone regulating several major physiological processes, including the circadian rhythm, pubertal development and seasonal adaptation. The two subtypes of mammalian G protein-coupled receptors utilize the same panel of G proteins for signal transduction but they appear to play different functional roles. Because synthetic melatonin agonists have a high therapeutic potential in modulating insomnia and circadian-related sleep disorders, the discovery and development of subtype-selective melatoninergic compounds is highly desirable. A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their receptor binding affinities towards human melatonin MT₁ and MT₂ receptors were evaluated by radioligand binding assay. Structure-activity relationship (SAR) analysis on potent subtype-selective ligands revealed that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT₂ binding affinity and at the same time decreased MT₁ binding affinity. The pharmacological potency and efficacy of these high affinity compounds were subsequently verified with FLIPR high-throughput screening, ERK phosphorylation and cAMP assays. Structural moieties conferring the subtype selectivity were defined, and extremely potent type 2 melatonin receptor-selective ligands have been generated by incorporating these features. These ligands represent invaluable tools for delineating the functional roles of distinct melatonin receptor subtypes.