Strategies for developing μ opioid receptor agonists with reduced adverse effects

被引：1

作者：

Yuan, Yan ^{[1
]}

Xu, Ting ^{[2
]}

Huang, Yu ^{[1
]}

Shi, Jianyou ^{[3
]}

机构：

[1] Southwest Jiaotong Univ, Coll Life Sci & Engn, Chengdu 611756, Sichuan, Peoples R China

[2] Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sch Med, Dept Anesthesiol, Chengdu 610072, Sichuan, Peoples R China

[3] Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sch Med, Dept Pharm, Chengdu 610072, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2024年 / 149卷

基金：

中国国家自然科学基金;

关键词：

mu opioid receptor(MOR) agonists; Small molecules; The design approaches; Structure -activity relationship; New low efficacy agonists; G alpha subtype; POSITIVE ALLOSTERIC MODULATORS; BIASED AGONISM; RESPIRATORY DEPRESSION; INDOLE ALKALOIDS; DISCOVERY; MORPHINE; PAIN; PHARMACOLOGY; ACTIVATION; LIGAND;

D O I：

10.1016/j.bioorg.2024.107507

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Opioids are currently the most effective and widely used painkillers in the world. Unfortunately, the clinical use of opioid analgesics is limited by serious adverse effects. Many researchers have been working on designing and optimizing structures in search of novel mu opioid receptor(MOR) agonists with improved analgesic activity and reduced incidence of adverse effects. There are many strategies to develop MOR drugs, mainly focusing on new low efficacy agonists (potentially G protein biased agonists), MOR agonists acting on different G alpha subtype, targeting opioid receptors in the periphery, acting on multiple opioid receptor, and targeting allosteric sites of opioid receptors, and others. This review summarizes the design methods, clinical applications, and structure-activity relationships of small-molecule agonists for MOR based on these different design strategies, providing ideas for the development of safer novel opioid ligands with therapeutic potential.

引用

页数：17

共 149 条

[1] Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential? [J].

Albert-Vartanian, A. ;

Boyd, M. R. ;

Hall, A. L. ;

Morgado, S. J. ;

Nguyen, E. ;

Nguyen, V. P. H. ;

Patel, S. P. ;

Russo, L. J. ;

Shao, A. J. ;

Raffa, R. B. .

JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS, 2016, 41 (04) :371-382

[2] THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets [J].

Alexander, Stephen P. H. ;

Kelly, Eamonn ;

Mathie, Alistair ;

Peters, John A. ;

Veale, Emma L. ;

Armstrong, Jane F. ;

Faccenda, Elena ;

Harding, Simon D. ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Buneman, O. Peter ;

Cidlowski, John A. ;

Christopoulos, Arthur ;

Davenport, Anthony P. ;

Fabbro, Doriano ;

Spedding, Michael ;

Striessnig, Joerg ;

Davies, Jamie A. .

BRITISH JOURNAL OF PHARMACOLOGY, 2019, 176 :S1-S20

[3] Contribution of G-Protein α-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine [J].

Araldi, Dioneia ;

Bonet, Ivan J. M. ;

Green, Paul G. ;

Levine, Jon D. .

JOURNAL OF NEUROSCIENCE, 2022, 42 (07) :1196-1210

[4] Opioid substitution to reduce adverse effects in cancer pain management [J].

Ashby, MA ;

Martin, P ;

Jackson, KA .

MEDICAL JOURNAL OF AUSTRALIA, 1999, 170 (02) :68-71

[5] The opioid crisis in North America: facts and future lessons for Europe [J].

Ayoo, Kennedy ;

Mikhaeil, John Sami ;

Huang, Alexander ;

Wasowicz, Marcin .

ANAESTHESIOLOGY INTENSIVE THERAPY, 2020, 52 (02) :139-147

[6] A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors [J].

Baamonde, Ana ;

Menendez, Luis ;

Gonzalez-Rodriguez, Sara ;

Lastra, Ana ;

Seitz, Viola ;

Stein, Christoph ;

Machelska, Halina .

SCIENTIFIC REPORTS, 2020, 10 (01)

[7]

Bartuzi D, 2018, METHODS MOL BIOL, V1705, P297, DOI 10.1007/978-1-4939-7465-8_13

[8] Evaluation of G protein bias and β-arrestin 2 signaling in opioid-induced respiratory depression [J].

Bateman, Jordan T. ;

Levitt, Erica S. .

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2021, 321 (04) :C681-C683

[9] Therapeutic Potential of Kappa Opioid Agonists [J].

Beck, Tyler C. ;

Hapstack, Matthew A. ;

Beck, Kyle R. ;

Dix, Thomas A. .

PHARMACEUTICALS, 2019, 12 (02)

[10] Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats [J].

Bergh, Marianne Skov-Skov ;

Bogen, Inger Lise ;

Garibay, Nancy ;

Baumann, Michael H. .

NEUROPHARMACOLOGY, 2019, 158

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