Design, synthesis, and biological activity of new endomorphin analogs with multi-site modifications

Bioorg Med Chem. 2020 May 1;28(9):115438. doi: 10.1016/j.bmc.2020.115438.

Long Zhao ¹, Keyao Luo ¹, Zhaojuan Wang ¹, Yuan Wang ², Xianghui Zhang ¹, Dongxu Yang ¹, Mengtao Ma ¹, Jingjing Zhou ¹, Jiaming Cui ¹, Jing Wang ¹, Chao-Zhen-Yi Han ¹, Xin Liu ³, Rui Wang ⁴

Affiliations

1 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Biochemistry and Molecular Biology, Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China.
2 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Biochemistry and Molecular Biology, Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China. Electronic address: yuanwang@lzu.edu.cn.
3 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Biochemistry and Molecular Biology, Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China. Electronic address: liuxinlz@lzu.edu.cn.
4 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Biochemistry and Molecular Biology, Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China. Electronic address: wangrui@lzu.edu.cn.

PMID: 32199689 DOI: 10.1016/j.bmc.2020.115438

Abstract

Endomorphin (EM)-1 and EM-2 are the most effective endogenous analgesics with efficient separation of analgesia from the risk of adverse effects. Poor metabolic stability and ineffective analgesia after peripheral administration were detrimental for the use of EMs as novel clinical analgesics. Therefore, here, we aimed to establish new EM analogs via introducing different bifunctional d-amino acids at position 2 of [(2-furyl)Map⁴]EMs. The combination of [(2-furyl)Map⁴]EMs with D-Arg² or D-Cit² yielded analogs with enhanced binding affinity to the μ-opioid receptor (MOR) and increased stability against enzymatic degradation (t_1/2 > 300 min). However, the agonistic activities of these analogs toward MOR were slightly reduced. Similar to morphine, peripheral administration of the analog [D-Cit², (2-furyl)Map⁴]EM-1 (10) significantly inhibited the pain behavior of mice in multiple pain models. In addition, this EM-1 analog was associated with reduced tolerance, less effect on gastrointestinal mobility, and no significant motor impairment. Compared to natural EMs, the EM analogs synthesized herein had enhanced metabolic stability, bioavailability, and analgesic properties.

Keywords

Adverse effect; Analgesia; Endomorphin; Motor impairment; μ-opioid receptor.

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