Novel bromomelatonin derivatives as potentially effective drugs to treat bone diseases

: Several reports indicate that melatonin is involved in the regulation of bone metabolism. To examine the direct effect of melatonin on osteoclasts and osteoblasts, we developed an in vitro assay using fish scales that contain osteoclasts, osteoblasts, and bone matrix, all of which are similar to those found in mammalian membrane bone. Using the assay, we demonstrated that melatonin suppressed osteoclastic and osteoblastic activities. These findings are in agreement with the reports from in vivo studies in mice and rats. In an attempt to develop molecules that increase bone mass, novel bromomelatonin derivatives were synthesized, and the effects of these chemicals on osteoclasts and osteoblasts using the scale assay were examined. As a result, novel bromomelatonin derivatives with the ability to possibly increase bone formation were identified. In scale osteoclasts, particularly, 1‐benzyl‐2,4,6‐tribromomelatonin had a more potent activity than melatonin. In reference to osteoblasts, this agent (10−9–10−6 m) significantly activated osteoblasts. The effect of 1‐benzyl‐2,4,6‐tribromomelatonin on bone formation was confirmed in ovariectomized rats. Thus, the oral administration of 1‐benzyl‐2,4,6‐tribromomelatonin augmented the total bone mineral density of the femoral metaphysis of ovariectomized rats. The stress–strain index of the diaphysis in 1‐benzyl‐2,4,6‐tribromomelatonin‐treated rats significantly increased in comparison with that in ovariectomized rats. In rats fed a low‐calcium diet, the total bone mineral density of the femoral metaphysis significantly increased following the oral administration of 1‐benzyl‐2,4,6‐tribromomelatonin. These studies identified a melatonin derivative that may have potential use in the treatment of bone diseases, such as osteoporosis.