Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.
Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.
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DOI：
10.1021/acs.jmedchem.5b01170
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发表时间：
2015-11-12
影响因子：
7.3
通讯作者：
Hruby VJ
中科院分区：
文献类型：
--
作者：
Giri AK;Apostol CR;Wang Y;Forte BL;Largent-Milnes TM;Davis P;Rankin D;Molnar G;Olson KM;Porreca F;Vanderah TW;Hruby VJ
设计并合成了具有μ/δ阿片受体激动剂活性(MOR/DOR)和神经激肽-1受体拮抗剂生物活性(NK1R)的多功能配体。与现有药物相比，这些基于多肽的配体有望产生更好的生物学特性(例如，更高的止痛效果和更少的不良反应)，并提供比多种药物混合物联合给药更好的协同效应。为了寻找在三种受体上具有预期活性的多功能配体，进行了系统的构效关系(SAR)研究。已经发现，在第一位引入2，6-二甲基酪氨酸(2，6-二甲基酪氨酸)，在第四位引入NMePhe(配体3：H-Dmt-D-Ala-Gly-NMePhe-Pro-Leu-Trp-NH-Bn(3′，5′-(CF3)2)))，在保持NK1R的效力、效力和拮抗剂活性的同时，显示出对MOR的结合和功能选择性。DMT在第一位，Phe(4-F)在第四位(配体5：H-Dmt-D-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3′，5′-(CF3)2))在MOR和DOR表现出平衡的结合亲和力，尽管它在DOR具有比MOR更高的激动剂活性。这项研究已经发现了几个新的配体，包括3和5，它们具有良好的体外生物活性。3、5和7(H-Tyr-D-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3′，5′-(CF3)2))配体在大鼠血浆中的代谢稳定性研究表明，它们的稳定性依赖于第一和第四位的修饰(3：T1/2和gt；24 h；5：t1/2≈6 h；7：t1/2和gt；2 h)。这两种配体的初步体内研究显示了良好的抗伤害活性。
Multifunctional ligands with agonist bioactivities at μ/δ opioid receptors (MOR/DOR) and antagonist bioactivity at the neurokinin-1 receptor (NK1R) have been designed and synthesized. These peptide-based ligands are anticipated to produce better biological profiles (e.g., higher analgesic effect with significantly less adverse side effects) compared to those of existing drugs and to deliver better synergistic effects than coadministration of a mixture of multiple drugs. A systematic structure–activity relationship (SAR) study has been conducted to find multifunctional ligands with desired activities at three receptors. It has been found that introduction of Dmt (2,6-dimethyl-tyrosine) at the first position and NMePhe at the fourth position (ligand 3: H-Dmt-D-Ala-Gly-NMePhe-Pro-Leu-Trp-NH-Bn(3′,5′-(CF3)2)) displays binding as well as functional selectivity for MOR over DOR while maintaining efficacy, potency, and antagonist activity at the NK1R. Dmt at the first position with Phe(4-F) at the fourth position (ligand 5: H-Dmt-D-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3′,5′-(CF3)2)) exhibits balanced binding affinities at MOR and DOR though it has higher agonist activity at DOR over MOR. This study has led to the discovery of several novel ligands including 3 and 5 with excellent in vitro biological activity profiles. Metabolic stability studies in rat plasma with ligands 3, 5, and 7 (H-Tyr-D-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3′,5′-(CF3)2)) showed that their stability depends on modifications at the first and fourth positions (3: T1/2 > 24 h; 5: T1/2 ≈ 6 h; 7: T1/2 > 2 h). Preliminary in vivo studies with these two ligands have shown promising antinociceptive activity.
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