基于肽类配体研制的依卢多林

发布时间：2018-04-24 06:37

本文选题：阿片受体 + 幸运之神　；参考：《药学学报》2015年08期

【摘要】：新药创制是复杂的智力活动,涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹,而构建化学结构是最重要的环节,因为它涵盖了药效、药代、安全性和生物药剂学等性质。本栏目以药物化学视角,对有代表性的药物的成功构建,加以剖析和解读。靶标蛋白的杂泛性是生物进化的一个标志,反映在药物的作用上,主作用往往伴随着副作用,新药的创制在于"扬善抑恶"。激动中枢的阿片受体可产生镇痛作用,而对外周的胃肠道则抑制蠕动产生便秘,后者可利用为治疗腹泻型肠易激综合征。研制依卢多林,定位于口服用药只作用于胃肠道的阿片受体,而不进入中枢神经,不被吸收,不穿越血脑屏障。以天然配体五肽为起点,削减成拟二肽,再经骨架迁越彻底去除肽的性质。用药物化学的理念和方法优化活性的同时,注重了药代的成药性。本品的成功或许还有幸运之神的佑助:对阿片μ和δ两个受体亚型呈完全相反的作用而相得益彰,较低的生物利用度也保障了本品局部作用的优势而少成瘾性,这些在理性设计中是未曾提及的。
[Abstract]:New drug creation is a complex intellectual activity involving multi-dimensional scientific and technological activities such as scientific research, technological creation, product development and medical effects. Each drug has its own R & D track, and the construction of chemical structures is the most important step because it covers pharmacodynamics, pharmacology, safety and biopharmaceutical properties. This column analyzes and interprets the successful construction of representative drugs from the perspective of drug chemistry. The heterogeneity of target proteins is a marker of biological evolution, reflected in the role of drugs, the main role is often accompanied by side effects, the creation of new drugs lies in "promote good against evil." The opioid receptor in the stimulation center can produce analgesic effect, while the peripheral gastrointestinal tract can inhibit peristalsis and constipation, the latter can be used to treat diarrhea irritable bowel syndrome. Eludolin was developed for oral administration of opioid receptors acting only on the gastrointestinal tract, without entering the central nervous system, not being absorbed, and not crossing the blood-brain barrier. Using the natural ligand pentapeptide as the starting point, the peptide was reduced to a dipeptide, and the properties of the peptide were removed thoroughly through the skeleton transfer. While optimizing the activity with the idea and method of pharmacochemistry, we pay attention to the drug generation. The success of this product may also be helped by the god of luck: the opioids 渭 and 未 receptor subtypes are completely opposite to each other, and the low bioavailability also guarantees the advantage of local action and less addiction. These are not mentioned in rational design.
【作者单位】：中国医学科学院药物研究所;
【分类号】：R943

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