碳循环集梅拉诺提德类似物在黑色皮质素4受体上保持生化功效
Samuel Gary1, Anuradha Roy2, Steven Bloom1
1Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA.
概括
研究人员通过用碳链接剂取代其二硫化键来修改对肥胖的类药物setmelanotide. 这提高了它的稳定性和透性,为治疗肥胖症创造了强大的MC4R激动剂.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 分子生物学分子生物学
背景情况:
- 黑色皮质素4受体 (MC4R) 对于调节和能量平衡至关重要.
- MC4R 调节失调与过和肥胖有关.
- 塞特梅拉诺提德是一种循环类药物,可激活MC4R治疗肥胖症,但在稳定性和脑透方面存在局限性.
研究的目的:
- 为了改善setmelanotide的药理动力学特性.
- 开发具有增强代谢稳定性和血脑屏障透性的新型MC4R激动剂.
- 探索用碳循环链接剂取代二硫化键对MC4R活性的影响.
主要方法:
- 使用冷电子显微镜的MC4R与setmelanotide结合的结构.
- 通过内部化学合成了11种setmelanotide的碳循环类似物.
- 在实验室中确定了在MC4R的同类物质的生物化学功效.
主要成果:
- 在11种合成的类似物中,有10种在MC4R.完全表现出对抗作用.
- 用各种碳循环连接剂 (基,基, perfluoroalkyl,乙烯基) 替换二硫化键是耐受良好的.
- 富含异性原子或芳香基的连接剂表现出更高的功效.
结论:
- 用基于碳的链接剂替换setmelanotide中的二硫化键是一种可行的策略,以增强药物动力学特性.
- 塞特梅拉诺提德的新型碳循环类似物保留了强大的MC4R激活活性.
- 这些发现为开发改善MC4R相关肥胖治疗方法提供了有希望的途径.
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