Mu Opioids and Their Receptors: Evolution of a Concept
01 Oct 2013-Pharmacological Reviews (American Society for Pharmacology and Experimental Therapeutics)-Vol. 65, Iss: 4, pp 1257-1317
TL;DR: 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.
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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.
Abstract: Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.
715 citations
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.
Abstract: Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 A X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2-adrenergic receptor (β2AR) and the M2 muscarinic receptor. Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, 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.
704 citations
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.
269 citations
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.
Abstract: Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our 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.
232 citations
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.
Abstract: Direct functionalization of natural products is important for studying the structure-activity and structure-property relationships of these molecules. Recent advances in the transition-metal-catalyzed functionalization of C(sp3 )-H bonds, the most abundant yet inert bonds in natural products, have allowed natural product derivatives to be created selectively. Strategies to achieve such transformation are reviewed.
224 citations
References
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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.
Abstract: 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. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.
7,538 citations
5,607 citations
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.
Abstract: Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structural features, including a bundle of seven transmembrane alpha helices connected by six loops of varying lengths. We determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution. The highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the seven-helix transmembrane motif. The ground-state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Interactions of the chromophore with a cluster of key residues determine the wavelength of the maximum absorption. Changes in these interactions among rhodopsins facilitate color discrimination. Identification of a set of residues that mediate interactions between the transmembrane helices and the cytoplasmic surface, where G-protein activation occurs, also suggests a possible structural change upon photoactivation.
5,357 citations
"Mu Opioids and Their Receptors: Evo..." refers background in this paper
...The structure of GPCRs was first extrapolated from rhodopsin (Palczewski et al., 2000) and the b2 receptor (Rasmussen et al....
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...The structure of GPCRs was first extrapolated from rhodopsin (Palczewski et al., 2000) and the b2 receptor (Rasmussen et al., 2011)....
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Book•
01 Jan 1985
TL;DR: Goodman and Gilman's the pharmacological basis of therapeutics , Goodman and Gilmann's the pharmaceutica basis for drug discovery, and more.
Abstract: In 1940, the world of pharmacology was revolutionized by the appearance of the first edition of this now-classic text. Edited by Lou Goodman and Al Gilman, it was a joy to read and a beacon in the darkness for teachers, students, and practitioners. (I can recall physicians saying they kept it on their bedside table for their nightly reading and pleasure.) The new edition remains a competently written and authoritative book, although it is now put together by 58 people instead of two, with the inevitable problems posed by such a division of labor. (One may envy the editors and the publishers the income from this best seller, but not the task of nagging recalcitrant authors with no respect for deadlines.) One may question, however, as in recent editions, the wisdom of combining a textbook for students and a reference for physicians. Those of us who teach second-year medical students
4,553 citations
"Mu Opioids and Their Receptors: Evo..." refers background in this paper
...Opiates decrease propulsive peristaltic contractions, while increasing circular muscle tone and intraluminal pressure (Reisine and Pasternak, 1996)....
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...…of the gene with the pharmacological evidence for subtypes of mu (Pasternak and Snyder, 1975b; Pasternak et al., 1980b; Wolozin and Pasternak, 1981), delta (Jiang et al., 1991), and kappa receptors (Zukin et al., 1988; Clark et al., 1989; Rothman et al., 1990; Reisine and Pasternak, 1996)....
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...Full descriptions of these are beyond the scope of this review, and readers are referred to a number of reviews (Cicero, 1980; Reisine and Pasternak, 1996; Pattinson, 2008; Diego et al., 2009, 2011; Cox, 2011; Elliott et al., 2011; Wald, 2012)....
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...The initial pharmacologic studies of opiates focused on the general effects of morphine in humans (reviewed by Martin, 1963, 1967; Reisine and Pasternak, 1996)....
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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.
Abstract: Enkephalin, a natural ligand for opiate receptors is composed of the pentapepides H-Tyr-Gly-Gly-Phe-Met-OH and H-Tyr-Gly-Gly-Phe-Leu-OH. 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.
3,580 citations
"Mu Opioids and Their Receptors: Evo..." refers background or methods in this paper
...Kosterlitz named the two pentapeptides the enkephalins, referring to their presence within the brain, whereas Avram Goldstein coined the term dynorphin for the 17mer he isolated based upon its very high potency....
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...Kosterlitz used the mouse vas deferens bioassay to identify the material and monitor its purification....
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...Early investigators found it easier to examine opiate mechanisms in isolated organ systems, such as the guinea pig ileum (Trendelenburg, 1917; Schaumann, 1955; Kosterlitz and Robinson, 1957a; Paton, 1957), and found that opiates inhibited the release of acetylcholine (Paton, 1957; Schaumann, 1957; Trendelenburg, 1957; Cox and Weinstock, 1966)....
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..., 1975a; Terenius and Wahlstrom, 1975), but these were rapidly followed by determination of the structure of the enkephalins by Kosterlitz (Hughes et al., 1975)....
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...It is said that after a single malt whisky or two Kosterlitz referred to dynorphin as an extended enkephalin, whereas Goldstein considered the enkephalins to be truncated dynorphins....
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