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
Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept
Li Xiao,Yujun Wang,Mumei Zhang,Wei-Wei Wu,Linghui Kong,Yan Ma,Yan Ma,Xue-Jun Xu,Xiao Liu,Qian He,Yuanyuan Qian,Huijiao Sun,Hai-hao Wu,Cheng Lin,Huoming Huang,Rongrong Ye,Shuang Jiang,Ru-Feng Ye,Congmin Yuan,Shengyang Fang,Dengqi Xue,Xicheng Yang,Hao Chen,Yilin Zheng,Linqian Yu,Qiong Xie,Lan Zheng,Wei Fu,Wei Li,Zhuibai Qiu,Jing-Gen Liu,Liming Shao +31 more
TL;DR: This compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H, and was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1 and E209EL2.
Journal ArticleDOI
Use of a Noninvasive Brain-Penetrating Peptide-Drug Conjugate Strategy to Improve the Delivery of Opioid Pain Relief Medications to the Brain.
Emilie Eiselt,Valérie Otis,Karine Belleville,Gaoqiang Yang,Alain Larocque,Anthony Regina,Michel Demeule,Philippe Sarret,Louis Gendron +8 more
TL;DR: New brain-penetrant opioid conjugates exhibiting improved analgesia to side effect ratios are developed and support the use of An2-carrier peptides as an innovative BBB-targeting technology to deliver effective drugs, such as M6G, for pain management.
Journal ArticleDOI
A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin
Martin Strack,Andrea Bedini,King Tuo Yip,Sara Lombardi,Daniel Siegmund,Raphael Stoll,Santi Spampinato,Nils Metzler-Nolte +7 more
TL;DR: In silico docking studies support receptor activation by both dermorphin binding modes and suggest a biological relevance for der Morphin itself, which is in line with previous protein mutation studies.
Journal ArticleDOI
In vitro and in vivo Pharmacological Activities of 14-O-Phenylpropyloxymorphone, a Potent Mixed Mu/Delta/Kappa-Opioid Receptor Agonist With Reduced Constipation in Mice.
TL;DR: POMO emerges as a new potent mixed mu/delta/kappa-opioid receptor agonist with reduced liability to cause constipation at antinociceptive doses and the pursuit for new opioids exhibiting a favorable dissociation between analgesia and adverse effects.
Journal ArticleDOI
Identification of Abundant and Evolutionarily Conserved Opioid Receptor Circular RNAs in the Nervous System Modulated by Morphine
Takeshi Irie,Rebecca Shum,Ioanna Deni,Amanda Hunkele,Valerie Le Rouzic,Jin Xu,Roger S. Wilson,Gregory W. Fischer,Gavril W. Pasternak,Ying-Xian Pan +9 more
TL;DR: It is reported that in addition to traditional linear mRNAs (linRNA), mouse, rat, and human opioid receptor genes generate exonic circRNA isoforms, and all members of the opioid receptor gene family express circRNAs, with Oprm1 circRNA levels exceeding those of linear forms in some regions.
References
More filters
Journal ArticleDOI
A Map of Human Genome Variation From Population-Scale Sequencing
Gonçalo R. Abecasis,David Altshuler,David Altshuler,Adam Auton,Lisa D Brooks,Richard Durbin,Richard A. Gibbs,Matthew E. Hurles,Gil McVean +8 more
TL;DR: The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype as mentioned in this paper, and the results of the pilot phase of the project, designed to develop and compare different strategies for genomewide sequencing with high-throughput platforms.
Journal ArticleDOI
Table S2: Trans-factors and trinucleotide repeat instability Trans-factor
Journal ArticleDOI
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Krzysztof Palczewski,Takashi Kumasaka,Tetsuya Hori,Craig A. Behnke,H. Motoshima,Brian A. Fox,I. Le Trong,David C. Teller,Tetsuji Okada,Ronald E. Stenkamp,Masaki Yamamoto,Masashi Miyano +11 more
TL;DR: This article determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution and found that the highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the sevenhelix transmembrane motif.
Book
Goodman & Gilman's The Pharmacological Basis of Therapeutics
TL;DR: Goodman and Gilman's the pharmacological basis of therapeutics , Goodman and Gilmann's the pharmaceutica basis for drug discovery, and more.
Journal ArticleDOI
Identification of two related pentapeptides from the brain with potent opiate agonist activity
John J. Hughes,T. W. Smith,H. W. Kosterlitz,Linda A. Fothergill,B. A. Morgan,Howard R. Morris +5 more
TL;DR: The evidence is based on the determination of the amino acid sequence of natural enkephalin by the dansyl–Edman procedure and by mass spectrometry followed by synthesis and comparison of the natural and synthetic peptides.
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