Mu Opioids and Their Receptors: Evolution of a Concept
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TLDR
Understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years, which now reveals a complexity of the morphine- like agents andtheir receptors that had not been previously appreciated.Abstract:
Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes—primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.read more
Citations
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Structure-based discovery of opioid analgesics with reduced side effects
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TL;DR: A 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment is reported, revealing an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.
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References
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Book ChapterDOI
5 Analgesics and their Antagonists: Biochemical Aspects and Structure-Activity Relationships
A.H. Beckett,A.F. Casy +1 more
TL;DR: It is evident that efforts to associate the analgesic properties of morphine with its effects upon functional systems within the body have so far been unsuccessful.
Journal ArticleDOI
Opioid peptide receptor studies, 11: involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands.
Heng Xu,Yi-Feng Lu,John S. Partilla,Qiao-Xi Zheng,Jia-Bei Wang,George A. Brine,F. Ivy Carroll,Kenner C. Rice,Kai-Xian Chen,Zhi-Qiang Chi,Richard B. Rothman +10 more
TL;DR: The role of weak electrostatic and hydrogen‐bonding “π‐π” interactions of the O atom of the carbonyl group and the phenyl ring structures of RTI‐4614–4 and its four enantiomers with residues Tyr148, Trp318, and His319 were explored via site‐directed mutagenesis and indicate the importance of Tyr148 and His 319 for the binding of fentanyl derivatives to the μ receptor.
Journal ArticleDOI
Synthesis and Biological Evaluation of 14‐Alkoxymorphinans. Part 8. 14‐methoxymetopon, an extremely potent opioid agonist
TL;DR: In this article, 14-Methoxymetopon (5,14-O-dimethyloxymorphone; 4) and 14-etoxy metopon(5) were synthesized from 14-hydroxy-5-methylcodeinone (6), which was found to be ca. 20 000 times more potent than morphine.
Journal ArticleDOI
Methadone analgesia in morphine-insensitive CXBK mice.
TL;DR: Different analgesic mechanisms for morphine and methadone are revealed and provide further support for multiple subtypes of mu-opioid receptors.
Journal ArticleDOI
Immunohistochemical study of the expression of EXON11-containing μ opioid receptor variants in mouse brain
TL;DR: The expression of exon 11-like immunoreactivity (-LI) was seen primarily in the olfactory tubercle, caudate-putamen, globus pallidus and substantia nigra, and the general pattern of labeling was diffuse, in contrast to the pattern seen with an exon 4-generated antiserum that labels MOR-1 itself.
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