Design, Synthesis, and Pharmacological Characterization of Novel Endomorphin-1 Analogues as Extremely Potent 渭-Opioid Agonists

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• 作者：Xin Liu ; Yuan Wang ; Yanhong Xing ; Jing Yu ; Hong Ji ; Ming Kai ; Zilong Wang ; Dan Wang ; Yixin Zhang ; Depeng Zhao ; Rui Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：3102-3114
• 全文大小：502K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

Recently we reported the synthesis and structure鈥揳ctivity study of endomorphin-1 (EM-1) analogues containing novel, unnatural 伪-methylene-尾-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt¹, (R/S)-尾Pro², and (ph)Map⁴/(2-furyl)Map⁴. All of the analogues showed a high affinity for the 渭-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt¹-(R)-尾Pro²-Trp³-(2-furyl)Map⁴ (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (K_i^渭 = 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, E_max = 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鈥揵rain barrier.