Design, synthesis, and pharmacological characterization of novel endomorphin-1 analogues as extremely potent μ-opioid agonists.
Design, synthesis, and pharmacological characterization of novel endomorphin-1 analogues as extremely potent μ-opioid agonists.
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DOI：
10.1021/jm400195y
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发表时间：
2013-03
影响因子：
7.3
通讯作者：
Xin Liu;Y. Wang;Yanhong Xing;Jing Yu;H. Ji;Ming Kai;Zilong Wang;Dan-dan Wang;Yixin Zhang-Yixin-Zhan
中科院分区：
文献类型：
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作者：
Xin Liu;Y. Wang;Yanhong Xing;Jing Yu;H. Ji;Ming Kai;Zilong Wang;Dan-dan Wang;Yixin Zhang-Yixin-Zhan
最近我们报道了一种含有新型非天然α-亚甲基-β-氨基丙酸（MAP）的内吗啡肽-1（EM-1）类似物的合成和结构活性研究。在本研究中，我们描述了新的EM-1类似物含有Dmt（1），（R/S）-βPro（2）和（ph）Map（4）/（2-呋喃基）Map（4）。所有的类似物都显示出对μ-阿片受体（莫尔）的高亲和力，并且在小鼠脑匀浆中的稳定性增加。在这些新化合物中，Dmt（1）-（R）-βPro（2）-Trp（3）-（2-呋喃基）Map（4）（类似物12）显示出对莫尔的最高亲和力，在皮摩尔范围内（Ki（μ）= 3.72 pM）。毛喉素诱导的cAMP积累试验表明，这种类似物显示出极高的激动效力，在亚皮摩尔范围内（EC 50 = 0.0421 pM，Emax = 99.5%）。当在甩尾试验中与吗啡相比时，该化合物在静脉内施用后也显示出更强的体内抗伤害感受活性，这表明该类似物能够穿过血脑屏障。
Recently we reported the synthesis and structure-activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural α-methylene-β-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-βPro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the μ-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-βPro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (Ki(μ) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, Emax = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier.