Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, 730000, P. R. China.
J Med Chem. 2012 Jul 12;55(13):6224-36. doi: 10.1021/jm300664y. Epub 2012 Jul 2.
A new class of endomorphin-1 (EM-1) analogues were synthesized by introduction of novel unnatural α-methylene-β-amino acids (Map) at position 3 or/and position 4. Their binding and functional activity, metabolic stability, and antinociceptive activity were determined and compared. Most of these analogues showed high affinities for the μ-opioid receptor and an increased stability in mouse brain homogenates compared with EM-1. Examination of cAMP accumulation and ERK1/2 phosphorylation in HEK293 cells confirmed the agonist properties of these analogues. Among these new analogues, H-Tyr-Pro-Trp-(2-furyl)Map-NH(2) (analogue 12) exhibited the highest binding potency (K(i)(μ) = 0.221 nM) and efficacy (EC(50) = 0.0334 nM, E(max) = 97.14%). This analogue also displayed enhanced antinociceptive activity in vivo in comparison to EM-1. Molecular modeling approaches were then carried out to demonstrate the interaction pattern of these analogues with the opioid receptors. We found that, compared to EM-1, the incorporation of our synthesized Map at position 4 would bring the analogue to a closer binding mode with the μ-opioid receptor.
研究人员通过在第 3 位或/和第 4 位引入新型非天然的α-亚甲基-β-氨基酸（Map），合成了一类新型内吗啡肽-1（EM-1）类似物。测定并比较了这些类似物的结合和功能活性、代谢稳定性和镇痛活性。与 EM-1 相比，这些类似物中的大多数对μ-阿片受体具有高亲和力，并且在小鼠脑匀浆中的稳定性增加。在 HEK293 细胞中检测 cAMP 积累和 ERK1/2 磷酸化证实了这些类似物的激动剂特性。在这些新类似物中，H-Tyr-Pro-Trp-(2-呋喃基)Map-NH(2)（类似物 12）表现出最高的结合效力（K(i)(μ) = 0.221 nM）和功效（EC(50) = 0.0334 nM，E(max) = 97.14%）。与 EM-1 相比，该类似物在体内也表现出增强的镇痛活性。然后进行了分子建模方法，以证明这些类似物与阿片受体的相互作用模式。我们发现，与 EM-1 相比，我们合成的 Map 位于 4 位会使类似物与μ-阿片受体的结合模式更加接近。
