Novel bromomelatonin derivatives suppress osteoclastic activity and increase osteoblastic activity: implications for the treatment of bone diseases
Novel bromomelatonin derivatives suppress osteoclastic activity and increase osteoblastic activity: implications for the treatment of bone diseases
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DOI：
10.1111/j.1600-079x.2007.00533.x
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发表时间：
2008-04
影响因子：
10.3
通讯作者：
N. Suzuki;M. Somei;K. Kitamura;R. Reiter;A. Hattori
中科院分区：
文献类型：
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作者：
N. Suzuki;M. Somei;K. Kitamura;R. Reiter;A. Hattori
摘要：硬骨鱼鳞片是一种钙化组织，含有破骨细胞、成骨细胞和骨基质，所有这些都与哺乳动物膜骨中发现的相似。使用金鱼鳞片，我们最近开发了一种新的体外测定系统，并在此之前证明，褪黑激素抑制骨细胞和成骨细胞的活动在此测定系统。在哺乳动物中，2-溴褪黑激素对褪黑激素受体的亲和力高于褪黑激素。使用新开发的合成方法，我们合成了2-溴褪黑激素、2，4，6-三溴褪黑激素和新型溴褪黑激素衍生物（1-烯丙基-2，4，6-三溴褪黑激素、1-炔丙基-2，4，6-三溴褪黑激素、1-苯甲基-2，4，6-三溴褪黑激素和2，4，6，7-四溴褪黑激素），然后检查这些化学物质对破骨细胞和成骨细胞的影响。所有溴褪黑素衍生物，以及褪黑激素，对破骨细胞有抑制作用。特别地，1-苄基-2，4，6-三溴褪黑素（苄基-三溴褪黑素）具有比褪黑素更强的活性。在体外浓度为10 - 10 mM时，苄基三溴褪黑素在孵育6小时后仍抑制骨细胞活性。关于成骨细胞，所有溴褪黑素衍生物有刺激作用，虽然褪黑激素抑制成骨细胞的活动。此外，雌激素受体mRNA表达（成骨细胞标志物）在苄基三溴褪黑素（10−7 m）处理的鳞片中增加。综上所述，本研究结果有力地表明，这些新的褪黑激素衍生物具有作为骨疾病如骨质疏松症的有益药物的显著潜力。
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.