Mu Opioids and Their Receptors: Evolution of a Concept
Reads0
Chats0
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
More filters
Journal ArticleDOI
Structure-based discovery of opioid analgesics with reduced side effects
Aashish Manglik,Henry Lin,Dipendra K. Aryal,John D. McCorvy,Daniela Dengler,Gregory Corder,Anat Levit,Ralf C. Kling,Ralf C. Kling,Viachaslau Bernat,Harald Hübner,Xi Ping Huang,Maria F. Sassano,Patrick M. Giguère,Stefan Löber,Da Duan,Grégory Scherrer,Brian K. Kobilka,Peter Gmeiner,Bryan L. Roth,Brian K. Shoichet +20 more
TL;DR: PZM21 is a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses.
Journal ArticleDOI
Structural insights into µ-opioid receptor activation
Weijiao Huang,Aashish Manglik,AJ Venkatakrishnan,Toon Laeremans,Evan N. Feinberg,Adrian L. Sanborn,Hideaki E. Kato,Kathryn E. Livingston,Thor S. Thorsen,Ralf C. Kling,Sébastien Granier,Peter Gmeiner,Stephen M. Husbands,John R. Traynor,William I. Weis,Jan Steyaert,Ron O. Dror,Brian K. Kobilka +17 more
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.
Journal ArticleDOI
Opioid-induced hyperalgesia: Cellular and molecular mechanisms.
TL;DR: The molecular actors identified include the Toll-like receptor 4 and the anti-opioid systems as well as some other excitatory molecules, receptors, channels, chemokines, pro-inflammatory cytokines or lipids, which contribute to OIH.
Journal ArticleDOI
Breaking barriers to novel analgesic drug development
TL;DR: Recent advances in the understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.
Journal ArticleDOI
Transition-Metal-Catalyzed Selective Functionalization of C(sp3 )-H Bonds in Natural Products.
TL;DR: Advances in the transition-metal-catalyzed functionalization of C(sp3 )-H bonds have allowed natural product derivatives to be created selectively and strategies to achieve such transformation are reviewed.
References
More filters
Journal ArticleDOI
Irreversible opiate agonists and antagonists: the 14- hydroxydihydromorphinone azines
TL;DR: Investigation into the molecular actions of the 14- hydroxydihydromorphinone hydrazones has suggested that their irreversible actions can be explained by the formation of their azines, which irreversibly block opiate binding in vitro 20- to 40-fold more potently than their corresponding hydrozones.
Journal ArticleDOI
Clinical experience of long-term treatment with epidural and intrathecal opioids--a nationwide survey.
TL;DR: In addition to dislocation, occlusion of the catheters or leakage, injection pain was an obstacle to successful treatment, and the highest daily morphine dose was 480 mg and 50 mg for epidural and intrathecal routes, respectively.
Journal ArticleDOI
Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden.
Gavin Bart,Markus Heilig,K S LaForge,Lotta Pollak,Suzanne M. Leal,Jurg Ott,Mary Jeanne Kreek,Mary Jeanne Kreek +7 more
TL;DR: Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden is found.
Journal ArticleDOI
Dermorphin analogues carrying an increased positive net charge in their "message" domain display extremely high mu opioid receptor selectivity.
TL;DR: The most selective compound was [D-Arg2,Lys4]dermorphin-(1-4)-amide (DALDA), showing a selectivity ratio more than 10 times higher than that of DAGO and, thus, displaying unprecedented mu-receptor specificity.
Journal ArticleDOI
In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions
Jane Dum,Albert Herz +1 more
TL;DR: Buprenorphine antagonized morphine antinociception at doses which normally have agonistic effects and produced maximum antagonistic effects at doses above those having prominent agonistic activity.
Related Papers (5)
Structural insights into µ-opioid receptor activation
Weijiao Huang,Aashish Manglik,AJ Venkatakrishnan,Toon Laeremans,Evan N. Feinberg,Adrian L. Sanborn,Hideaki E. Kato,Kathryn E. Livingston,Thor S. Thorsen,Ralf C. Kling,Sébastien Granier,Peter Gmeiner,Stephen M. Husbands,John R. Traynor,William I. Weis,Jan Steyaert,Ron O. Dror,Brian K. Kobilka +17 more
Structure-based discovery of opioid analgesics with reduced side effects
Aashish Manglik,Henry Lin,Dipendra K. Aryal,John D. McCorvy,Daniela Dengler,Gregory Corder,Anat Levit,Ralf C. Kling,Ralf C. Kling,Viachaslau Bernat,Harald Hübner,Xi Ping Huang,Maria F. Sassano,Patrick M. Giguère,Stefan Löber,Da Duan,Grégory Scherrer,Brian K. Kobilka,Peter Gmeiner,Bryan L. Roth,Brian K. Shoichet +20 more