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Biased mu-opioid receptor agonists confer analgesia with reduced side effects

Chloe Gui, Sean Wong
2018 University of Western Ontario Medical Journal  
Along with the analgesic benefits, opioid use also commonly induces a number of side effects. Respiratory depression is an especially dangerous and potentially lethal example.  ...  Downstream to the mu-opioid receptor, which is responsible for the analgesic effects of opioids, β-arrestin-2 signaling has been suggested to be important for the manifestation of side effects, including  ...  Biased mu-opioid receptor agonists confer analgesia with reduced side effects Chloe Gui, Sean Wong current limitations of opioids Though opioid addiction has been described as early as the sixteenth century  ... 
doi:10.5206/uwomj.v87i1.1910 fatcat:r2iboy25lbfrpcouylpxsc2emu

The Use of Computational Approaches in the Discovery and Mechanism Study of Opioid Analgesics

Bangyi Zhao, Wei Li, Lijie Sun, Wei Fu
2020 Frontiers in Chemistry  
Herein, we reviewed the computational-guided studies on opioid receptors for the discovery of new analgesics, the structural basis of receptor subtype selectivity, agonist interaction mechanism, and biased  ...  In the past few years, published high-resolution crystal structures of opioid receptor laid a solid basis for both experimental and computational studies.  ...  modification of this manuscript.  ... 
doi:10.3389/fchem.2020.00335 pmid:32500054 pmcid:PMC7242749 fatcat:aohqt6wzsjap3n4wrnkrwkegty

Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain

Keith M Olson, Wei Lei, Attila Keresztes, Justin LaVigne, John M Streicher
2017 The Yale Journal of Biology and Medicine  
Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid  ...  Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may  ...  valid targets for drug discovery to reduce opioid side effects.  ... 
pmid:28356897 pmcid:PMC5369049 fatcat:5pgcyk4jpnc5zfb5xkb7atxz3q

Biased agonism

M. Alexander Stanczyk, Ram Kandasamy
2018 PAIN Reports  
They find that increased bias towards G-protein signaling produces better antinociception with minimal side effects in mice models. G-protein-biased opioids may provide a safer treatment strategy.  ...  Opioids alleviate pain, but adverse effects severely limit their usefulness.  ...  in opioid-based analgesic drug discovery is biased agonism.  ... 
doi:10.1097/pr9.0000000000000650 pmid:29922742 pmcid:PMC5999417 fatcat:4qbjk7aldva67pi3qo22tjz73a

Biased ligands at opioid receptors: Current status and future directions

Tao Che, Hemlata Dwivedi-Agnihotri, Arun K. Shukla, Bryan L. Roth
2021 Science Signaling  
We also discuss an example of structure-based biased ligand discovery at the μ-opioid receptor, an approach that could revolutionize drug discovery at opioid and other receptors.  ...  effects of current opioid medications.  ...  A potential framework to overcome opioid side effects has emerged in the last decade based on the design and discovery of functionally selective ligands at opioid receptors.  ... 
doi:10.1126/scisignal.aav0320 pmid:33824179 pmcid:PMC7611221 fatcat:dkbbdswtdnfsbde6gnho7ygfzi

Designing Safer Analgesics via μ-Opioid Receptor Pathways

H.C. Stephen Chan, Dillon McCarthy, Jianing Li, Krzysztof Palczewski, Shuguang Yuan
2017 TIPS - Trends in Pharmacological Sciences  
In this review we outline recent progress towards the discovery of safer opioid analgesics.  ...  It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects.  ...  Unlike morphine and codeine, novel μOR agonists, such as PZM21 [28] and TRV130 [65] , retain most the opioid analgesic effects but with reduced toxic side effects, in part because of their biased agonism  ... 
doi:10.1016/j.tips.2017.08.004 pmid:28935293 pmcid:PMC5690544 fatcat:rpftdsj3xzghtntkysn4gveehq

Is tapentadol different from classical opioids? A review of the evidence

Richard M Langford, Roger Knaggs, Paul Farquhar-Smith, Anthony H Dickenson
2016 British Journal of Pain  
The reduced incidence of some of the typical opioid induced side-effects, compared to equianalgesic doses of classical opioids supports the hypothesis that tapentadol analgesia is only partially mediated  ...  Preclinical studies suggest that this combined and synergistic MOR and NRI activity might translate to an ability to be effective in a wide range of painful conditions with reduced opioid related side  ... 
doi:10.1177/2049463716657363 pmid:27867511 pmcid:PMC5102094 fatcat:gqeukihlbfamxgyxxbunvg5xm4

Opioid receptors: toward separation of analgesic from undesirable effects

Ping-Yee Law, Patricia H. Reggio, Horace H. Loh
2013 TIBS -Trends in Biochemical Sciences. Regular ed  
Recently, attempts to develop analgesic agents with reduced side effects have targeted either the putative opioid receptor splice variants or the receptor heterooligomers.  ...  This review discusses the potential for receptor splice variant-and the hetero-oligomer-based discovery of new opioid analgesics.  ...  We also examine alternative approaches in reducing the side effects of opioid drugs.  ... 
doi:10.1016/j.tibs.2013.03.003 pmid:23598157 pmcid:PMC3665630 fatcat:odm2jg2vhnaq5h72u4kyuz42su

A "tail" of opioid receptor variants

Stephanie Puig, Howard B. Gutstein
2017 Journal of Clinical Investigation  
This discovery greatly improves our understanding of opioid side effects and suggests intriguing therapeutic approaches that could improve both the safety and long-term effectiveness of opioids. observed  ...  This study adds additional support to the growing body of evidence that the desirable analgesic effects of opioids can be dissociated from undesirable side effects.  ... 
doi:10.1172/jci93582 pmid:28319052 pmcid:PMC5373875 fatcat:vfdfoupp55bvjcr4bffcop4tyy

A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor

Zoltan Dekan, Setareh Sianati, Arsalan Yousuf, Katy J. Sutcliffe, Alexander Gillis, Christophe Mallet, Paramjit Singh, Aihua H. Jin, Anna M. Wang, Sarasa A. Mohammadi, Michael Stewart, Ranjala Ratnayake (+10 others)
2019 Proceedings of the National Academy of Sciences of the United States of America  
Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.  ...  Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (Ki low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid  ...  This work was supported by Program Grant APP1072113 from the National Health and Medical Research Council of Australia (to P.F.A. and M.J.C.).  ... 
doi:10.1073/pnas.1908662116 pmid:31611414 pmcid:PMC6825270 fatcat:xgvua6aswbbolli2dq73vfhqya

Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics

Andrea Bedini, Elisabetta Cuna, Monica Baiula, Santi Spampinato
2022 International Journal of Molecular Sciences  
Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved  ...  complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics.  ...  opioid analgesic with increased efficacy/safety and lower side effects.  ... 
doi:10.3390/ijms23095114 pmid:35563502 pmcid:PMC9104178 fatcat:p2prttqsf5d2fiu5u36keehhh4

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

Joaquim Azevedo Neto, Anna Costanzini, Roberto De Giorgio, David G. Lambert, Chiara Ruzza, Girolamo Calò
2020 Molecules  
with reduced side effects or 'apparent bias'.  ...  Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs  ...  −) animals [18, 24] that βarr2 signaling is involved in the acute side effects of opioid analgesics.  ... 
doi:10.3390/molecules25173870 pmid:32854452 fatcat:kr2dlayrdnh43ef6zhvdz5tkxe

Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

Mariana Spetea, Helmut Schmidhammer
2021 Molecules  
Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with  ...  We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid  ...  opioid analgesics with fewer unwanted side effects compared to currently available pain therapeutics.  ... 
doi:10.3390/molecules26185677 pmid:34577147 pmcid:PMC8464912 fatcat:cjtcb7rkibbepgyz4ec2pvpifq

A new splice of life for the μ-opioid receptor

Michael J. Iadarola, Matthew R. Sapio, Andrew J. Mannes
2015 Journal of Clinical Investigation  
Acknowledgments This research was supported by the Intramural Research Program of the Clinical Center, NIH.  ...  in the quest for a strong analgesic with a reduced side effect profile.  ...  This observation led to the idea that these biased agonists of opioid receptors could be used to elicit the desired pain-reducing effects of opiates with minimal or no side effects.  ... 
doi:10.1172/jci82060 pmid:26011639 pmcid:PMC4563694 fatcat:beqjexxhv5dnzpabcgvjrq5hhm

Analgesic Potential of Extracts and Derived Natural Products from Medicinal Plants [chapter]

Abdur Rauf, Noor Jehan, Zarka Ahmad, Mohammad S. Mubarak
2017 Pain Relief - From Analgesics to Alternative Therapies  
Chemically diverse structures have been identified as pain relievers; they relieve pain through various mechanisms and act either centrally (opioids receptor agonism) or peripherally.  ...  Therefore, this chapter is intended to summarize the literature pertaining to plants and their constituents discovered with analgesic potential in the last four decades.  ...  Acknowledgements The authors are grateful to the Higher Education Commission of Pakistan and the University of Swabi, KPK, for financial support.  ... 
doi:10.5772/intechopen.68631 fatcat:hbjczqcbprfqbgcoa66yvupoga
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