Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
Department of Neuropeptides, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
Molecules. 2021 Dec 28;27(1):151. doi: 10.3390/molecules27010151.
Our formerly described pentapeptide opioid analog Tyr-c[D-Lys-Phe-Phe-Asp]NH (designated ), showing high affinity for the mu (MOR) and kappa (KOR) opioid receptors, was much more stable than endomorphine-2 (EM-2) in the rat brain homogenate and displayed remarkable antinociceptive activity after central (intracerebroventricular) and peripheral (intravenous ) administration. In this report, we describe the further modification of this analog, which includes the incorporation of a β-amino acid, ()- and ()-β-Lys, instead of D-Lys in position 2. The influence of such replacement on the biological properties of the obtained analogs, Tyr-c[()-β-Lys-Phe-Phe-Asp]NH () and Tyr-c[()-β-Lys-Phe-Phe-Asp]NH, (), was investigated in vitro. Receptor radiolabeled displacement and functional calcium mobilization assays were performed to measure binding affinity and receptor activation of the new analogs. The obtained data revealed that only one of the diastereoisomeric peptides, , was able to selectively bind and activate MOR. Molecular modeling (docking and molecular dynamics (MD) simulations) suggests that both compounds should be accommodated in the MOR binding site. However, in the case of the inactive isomer , fewer hydrogen bonds, as well as instability of the canonical ionic interaction to Asp, could explain its very low MOR affinity.
我们之前描述的五肽阿片样肽类似物 Tyr-c[D-Lys-Phe-Phe-Asp]NH（命名为），对 μ（MOR）和 κ（KOR）阿片受体具有高亲和力，在大鼠脑匀浆中比内吗啡肽-2（EM-2）稳定得多，并在中枢（脑室内）和外周（静脉内）给药后表现出显著的镇痛活性。在本报告中，我们描述了对该类似物的进一步修饰，包括在 2 位引入 β-氨基酸，()-和()-β-Lys，而不是 D-Lys。这种取代对获得的类似物的生物学性质的影响，Tyr-c[()-β-Lys-Phe-Phe-Asp]NH () 和 Tyr-c[()-β-Lys-Phe-Phe-Asp]NH，()，在体外进行了研究。进行了受体放射性标记置换和功能性钙动员测定，以测量新类似物的结合亲和力和受体激活。获得的数据表明，只有一种非对映异构体肽，，能够选择性地结合和激活 MOR。分子建模（对接和分子动力学（MD）模拟）表明，这两种化合物都应该能够适应 MOR 结合位点。然而，对于非活性异构体，由于氢键较少，以及 Asp 的经典离子相互作用不稳定，可能解释了其对 MOR 的亲和力非常低。
