本文選題：阿片受體 + 幸運(yùn)之神��； 參考：《藥學(xué)學(xué)報》2015年08期

【摘要】：新藥創(chuàng)制是復(fù)雜的智力活動,涉及科學(xué)研究、技術(shù)創(chuàng)造、產(chǎn)品開發(fā)和醫(yī)療效果等多維科技活動。每個藥物都有自身的研發(fā)軌跡,而構(gòu)建化學(xué)結(jié)構(gòu)是最重要的環(huán)節(jié),因?yàn)樗w了藥效、藥代、安全性和生物藥劑學(xué)等性質(zhì)。本欄目以藥物化學(xué)視角,對有代表性的藥物的成功構(gòu)建,加以剖析和解讀。靶標(biāo)蛋白的雜泛性是生物進(jìn)化的一個標(biāo)志,反映在藥物的作用上,主作用往往伴隨著副作用,新藥的創(chuàng)制在于"揚(yáng)善抑惡"。激動中樞的阿片受體可產(chǎn)生鎮(zhèn)痛作用,而對外周的胃腸道則抑制蠕動產(chǎn)生便秘,后者可利用為治療腹瀉型腸易激綜合征。研制依盧多林,定位于口服用藥只作用于胃腸道的阿片受體,而不進(jìn)入中樞神經(jīng),不被吸收,不穿越血腦屏障。以天然配體五肽為起點(diǎn),削減成擬二肽,再經(jīng)骨架遷越徹底去除肽的性質(zhì)。用藥物化學(xué)的理念和方法優(yōu)化活性的同時,注重了藥代的成藥性。本品的成功或許還有幸運(yùn)之神的佑助:對阿片μ和δ兩個受體亞型呈完全相反的作用而相得益彰,較低的生物利用度也保障了本品局部作用的優(yōu)勢而少成癮性,這些在理性設(shè)計中是未曾提及的。
[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.
【作者單位】： 中國醫(yī)學(xué)科學(xué)院藥物研究所;
【分類號】：R943

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本文編號：1795549