title: Characterization of substituted phenylpropylamides as highly selective agonists at the melatonin MT2 receptor.
abstract: 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.
authors.affiliation: Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: King H
authors.initials: KH
authors.lastname: Chan
authors.forename: Yueqing
authors.initials: Y
authors.lastname: Hu
authors.forename: Maurice K C
authors.initials: MK
authors.lastname: Ho
authors.forename: Yung H
authors.initials: YH
authors.lastname: Wong
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D008550:Melatonin / Q000378:metabolism*; D015394:Molecular Structure; D010649:Phenylalanine / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D044123:Receptor, Melatonin, MT2 / Q000819:agonists*
chemical_list: D000577:Amides; D008024:Ligands; D044123:Receptor, Melatonin, MT2; D010649:Phenylalanine; D008550:Melatonin