title: Novel bromomelatonin derivatives suppress osteoclastic activity and increase osteoblastic activity: implications for the treatment of bone diseases.
abstract: The teleost scale is a calcified tissue that contains osteoclasts, osteoblasts, and bone matrix, all of which are similar to those found in mammalian membrane bone. Using the goldfish scale, we recently developed a new in vitro assay system and previously demonstrated that melatonin suppressed both osteoclastic and osteoblastic activities in this assay system. In mammals, 2-bromomelatonin possesses a higher affinity for the melatonin receptor than does melatonin. Using a newly developed synthetic method, we synthesized 2-bromomelatonin, 2,4,6-tribromomelatonin and novel bromomelatonin derivatives (1-allyl-2,4,6-tribromomelatonin, 1-propargyl-2,4,6-tribromomelatonin, 1-benzyl-2,4,6-tribromomelatonin, and 2,4,6,7-tetrabromomelatonin) and then examined the effects of these chemicals on osteoclasts and osteoblasts. All bromomelatonin derivatives, as well as melatonin, had an inhibitory action on osteoclasts. In particular, 1-benzyl-2,4,6-tribromomelatonin (benzyl-tribromomelatonin) possessed a stronger activity than melatonin. At an in vitro concentration of 10(-10) m, benzyl-tribromomelatonin still suppressed osteoclastic activity after 6 hr of incubation. In reference to osteoblasts, all bromomelatonin derivatives had a stimulatory action, although melatonin inhibited osteoblastic activity. In addition, estrogen receptor mRNA expression (an osteoblastic marker) was increased in benzyl-tribromomelatonin (10(-7) m)-treated scales. Taken together, the present results strongly suggest that these novel melatonin derivatives have significant potential for use as beneficial drug for bone diseases such as osteoporosis.
authors.affiliation: Noto Marine Laboratory, Institute of Nature and Environmental Technology, Kanazawa University, Housu-gun, Ishikawa, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Suzuki
authors.forename: Masanori
authors.initials: M
authors.lastname: Somei
authors.forename: Kei-Ichiro
authors.initials: K
authors.lastname: Kitamura
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hattori
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003238:Connective Tissue / Q000187:drug effects / Q000502:physiology; D005260:Female; D006054:Goldfish; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects*; D010010:Osteoclasts / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis
chemical_list: D012333:RNA, Messenger; D011960:Receptors, Estrogen; C528516:benzyl-tribromomelatonin; C075920:2-bromomelatonin; D008550:Melatonin