A dual nociceptin and mu opioid receptor agonist exhibited robust antinociceptive effect with decreased side effects

Ying-Ting Hsu; Shen-Ren Chen; Yung-Chiao Chang; Hsiao-Fu Chang; Teng-Kuang Yeh; Jian-Ying Chuang; Horace H Loh; Hsing-Pang Hsieh; Shau-Hua Ueng; Shiu-Hwa Yeh

doi:10.1016/j.ejmech.2023.115608

A dual nociceptin and mu opioid receptor agonist exhibited robust antinociceptive effect with decreased side effects

Eur J Med Chem. 2023 Oct 5:258:115608. doi: 10.1016/j.ejmech.2023.115608. Epub 2023 Jul 1.

Authors

Affiliations

¹ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan, ROC; The Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan, ROC.
² Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan, ROC.
³ The Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan, ROC.
⁴ Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 10005, China; Department of Pharmacology, Medical School University of Minnesota, Minneapolis, MN, 55455-0217, USA.
⁵ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan, ROC; School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan, ROC. Electronic address: shueng@nhri.edu.tw.
⁶ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan, ROC; The Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan, ROC. Electronic address: bau9763@nhri.edu.tw.

PMID: 37437352
DOI: 10.1016/j.ejmech.2023.115608

Abstract

The compelling demand of a consummate analgesic medication without addiction is rising due to the clinical mistreatment. Additionally, the series of severe untoward effects usually deterred the utilization while coping with serious pain. As a possible turning point, we revealed that compound 14 is a dual agonist of mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor in this study. More importantly, compound 14 achieves pain relieving at very small doses, meanwhile, reduces several unwanted side effects such as constipation, reward, tolerance and withdrawal effects. Here, we evaluated the antinociception and side effects of this novel compound from wild type and humanized mice to further develop a safer prescription analgesic drug.

Keywords: Addiction; Antinociception; Antinociceptive tolerance; Constipation; Mu-opioid receptor; Reward effect.

MeSH terms

Analgesics / adverse effects
Analgesics, Opioid / adverse effects
Animals
Drug-Related Side Effects and Adverse Reactions*
Mice
Nociceptin
Nociceptin Receptor
Opioid Peptides / pharmacology
Opioid Peptides / therapeutic use
Pain / chemically induced
Pain / drug therapy
Receptors, Opioid / agonists
Receptors, Opioid, mu* / agonists

Substances

Receptors, Opioid, mu
Receptors, Opioid
Nociceptin Receptor
Opioid Peptides
Analgesics, Opioid
Analgesics