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Novel Mu Agonists

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https://www.readbyqxmd.com/read/27824891/exploring-flexibility-of-progesterone-receptor-ligand-binding-domain-using-molecular-dynamics
#1
Liangzhen Zheng, Valerie Chunling Lin, Yuguang Mu
Progesterone receptor (PR), a member of nuclear receptor (NR) superfamily, plays a vital role for female reproductive tissue development, differentiation and maintenance. PR ligand, such as progesterone, induces conformation changes in PR ligand binding domain (LBD), thus mediates subsequent gene regulation cascades. PR LBD may adopt different conformations upon an agonist or an antagonist binding. These different conformations would trigger distinct transcription events. Therefore, the dynamics of PR LBD would be of general interest to biologists for a deep understanding of its structure-function relationship...
2016: PloS One
https://www.readbyqxmd.com/read/27573832/a-novel-orvinol-analog-bu08028-as-a-safe-opioid-analgesic-without-abuse-liability-in-primates
#2
Huiping Ding, Paul W Czoty, Norikazu Kiguchi, Gerta Cami-Kobeci, Devki D Sukhtankar, Michael A Nader, Stephen M Husbands, Mei-Chuan Ko
Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27556704/mitragynine-corynantheidine-pseudoindoxyls-as-opioid-analgesics-with-mu-agonism-and-delta-antagonism-which-do-not-recruit-%C3%AE-arrestin-2
#3
András Váradi, Gina F Marrone, Travis C Palmer, Ankita Narayan, Márton R Szabó, Valerie Le Rouzic, Steven G Grinnell, Joan J Subrath, Evelyn Warner, Sanjay Kalra, Amanda Hunkele, Jeremy Pagirsky, Shainnel O Eans, Jessica M Medina, Jin Xu, Ying-Xian Pan, Attila Borics, Gavril W Pasternak, Jay P McLaughlin, Susruta Majumdar
Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism...
September 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27356522/the-abuse-potential-of-prescription-opioids-in-humans-closing-in-on-the-first-century-of-research
#4
Sharon L Walsh, Shanna Babalonis
While opioids are very effective analgesics for treating acute pain, humans have struggled with opiate addiction for millenia. An opium abuse epidemic in the early 1900's led the US government to develop a systematic research infrastructure and scientific plan to produce new compounds with analgesic properties but without abuse liability. This review describes the techniques that were developed for testing in the human laboratory, including empirically derived outcome measures and required elements for human abuse potential assessment...
June 30, 2016: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/27311393/increase-in-caveolae-and-caveolin-1-expression-modulates-agonist-induced-contraction-and-store-and-receptor-operated-ca-2-entry-in-pulmonary-arteries-of-pulmonary-hypertensive-rats
#5
Hai-Xia Jiao, Yun-Ping Mu, Long-Xin Gui, Fu-Rong Yan, Da-Cen Lin, James S K Sham, Mo-Jun Lin
Caveolin-1 (Cav-1) is a major component protein associated with caveolae in the plasma membrane and has been identified as a regulator of store-operated Ca(2+) entry (SOCE) and receptor-operated Ca(2+) entry (ROCE). However, the contributions of caveolae/Cav-1 of pulmonary arterial smooth muscle cells (PASMCs) to the altered Ca(2+) signaling pathways in pulmonary arteries (PAs) during pulmonary hypertension (PH) have not been fully characterized. The present study quantified caveolae number and Cav-1 expression, and determined the effects of caveolae disruption on ET-1, cyclopiazonic acid (CPA) and 1-Oleoyl-2-acetyl-glycerol (OAG)-induced contraction in PAs and Ca(2+) influx in PASMCs of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH rats...
September 2016: Vascular Pharmacology
https://www.readbyqxmd.com/read/27272042/characterisation-of-the-novel-mixed-mu-nop-peptide-ligand-dermorphin-n-ofq-deno
#6
Mark F Bird, Maria Camilla Cerlesi, Mark Brown, Davide Malfacini, Vanessa Vezzi, Paola Molinari, Laura Micheli, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Remo Guerrini, Girolamo Calò, David G Lambert
INTRODUCTION: Opioid receptors are currently classified as Mu (μ), Delta (δ), Kappa (κ) plus the opioid related nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP). Despite compelling evidence for interactions and benefits of targeting more than one receptor type in producing analgesia, clinical ligands are Mu agonists. In this study we have designed a Mu-NOP agonist named DeNo. The Mu agonist component is provided by dermorphin, a peptide isolated from the skin of Phyllomedusa frogs and the NOP component by the endogenous agonist N/OFQ...
2016: PloS One
https://www.readbyqxmd.com/read/27241845/antitumor-efficacy-of-radiation-plus-immunotherapy-depends-upon-dendritic-cell-activation-of-effector-cd8-t-cells
#7
Simon J Dovedi, Grazyna Lipowska-Bhalla, Stephen A Beers, Eleanor J Cheadle, Lijun Mu, Martin J Glennie, Timothy M Illidge, Jamie Honeychurch
Tumor cells dying after cytotoxic therapy are a potential source of antigen for T-cell priming. Antigen-presenting cells (APC) can cross-present MHC I-restricted peptides after the uptake of dying cells. Depending on the nature of the surrounding environmental signals, APCs then orchestrate a spectrum of responses ranging from immune activation to inhibition. Previously, we had demonstrated that combining radiation with either agonistic monoclonal antibody (mAb) to CD40 or a systemically administered TLR7 agonist could enhance CD8 T-cell-dependent protection against syngeneic murine lymphoma models...
July 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27217214/activation-of-the-adenosine-a2a-receptor-attenuates-experimental-autoimmune-encephalomyelitis-and-is-associated-with-increased-intracellular-calcium-levels
#8
Yumei Liu, Haifeng Zou, Ping Zhao, Bo Sun, Jinghua Wang, Qingfei Kong, Lili Mu, Sihan Zhao, Guangyou Wang, Dandan Wang, Yao Zhang, Jiaying Zhao, Pengqi Yin, Lei Liu, Xiuli Zhao, Hulun Li
Multiple sclerosis (MS) is a common autoimmune disease that inevitably causes inflammatory nerve demyelination. However, an effective approach to prevent its course is still lacking and urgently needed. Recently, the adenosine A2A receptor (A2AR) has emerged as a novel inflammation regulator. Manipulation of A2AR activity may suppress the MS process and protect against nerve damage. To test this hypothesis, we treated murine experimental autoimmune encephalomyelitis (EAE), a model for MS, with the selective A2AR agonist, CGS21680 (CGS)...
August 25, 2016: Neuroscience
https://www.readbyqxmd.com/read/27192616/synthetic-and-receptor-signaling-explorations-of-the-mitragyna-alkaloids-mitragynine-as-an-atypical-molecular-framework-for-opioid-receptor-modulators
#9
Andrew C Kruegel, Madalee M Gassaway, Abhijeet Kapoor, András Váradi, Susruta Majumdar, Marta Filizola, Jonathan A Javitch, Dalibor Sames
Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties...
June 1, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27136675/characterization-of-mudeng-a-novel-anti-apoptotic-protein
#10
J-H Choi, J-B Lim, D D Wickramanayake, Y Wagley, J Kim, H-C Lee, H G Seo, T-H Kim, J-W Oh
MUDENG (Mu-2-related death-inducing gene, MuD) is revealed to be involved in cell death signaling. Astrocytes, the major glial cell type in the central nervous system, are a source of brain tumors. In this study, we examined MuD expression and function in human astroglioma cells. Stimulation of U251-MG cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in a 40% decrease in cell viability and a 33% decrease in MuD protein levels, although not in MuD mRNA levels. To study the functional relevance of MuD expression, stable transfectants expressing high levels of MuD were generated...
2016: Oncogenesis
https://www.readbyqxmd.com/read/27075428/gi-protein-coupled-5-ht1b-d-receptor-agonist-sumatriptan-induces-type-i-hyperalgesic-priming
#11
Dioneia Araldi, Luiz F Ferrari, Jon D Levine
We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical hyperalgesia...
August 2016: Pain
https://www.readbyqxmd.com/read/27035329/novel-analogues-of-r-5-methylamino-5-6-dihydro-4h-imidazo-4-5-1-ij-quinolin-2-1h-one-sumanirole-provide-clues-to-dopamine-d2-d3-receptor-agonist-selectivity
#12
Mu-Fa Zou, Thomas M Keck, Vivek Kumar, Prashant Donthamsetti, Mayako Michino, Caitlin Burzynski, Catherine Schweppe, Alessandro Bonifazi, R Benjamin Free, David R Sibley, Aaron Janowsky, Lei Shi, Jonathan A Javitch, Amy Hauck Newman
Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D2/D3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [(3)H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [(3)H]N-methylspiperone. Although 1 was confirmed as a D2R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both GoBRET and mitogenesis functional assays...
April 14, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26974438/control-of-methicillin-resistant-staphylococcus-aureus-pneumonia-utilizing-tlr2-agonist-pam3csk4
#13
Yi-Guo Chen, Yong Zhang, Lin-Qiang Deng, Hui Chen, Yu-Juan Zhang, Nan-Jin Zhou, Keng Yuan, Li-Zhi Yu, Zhang-Hua Xiong, Xiao-Mei Gui, Yan-Rong Yu, Xiao-Mu Wu, Wei-Ping Min
The spread of methicillin-resistant Staphylococcus aureus (MRSA) is a critical health issue that has drawn greater attention to the potential use of immunotherapy. Toll-like receptor 2 (TLR2), a pattern recognition receptor, is an essential component in host innate defense system against S. aureus infection. However, little is known about the innate immune response, specifically TLR2 activation, against MRSA infection. Here, we evaluate the protective effect and the mechanism of MRSA murine pneumonia after pretreatment with Pam3CSK4, a TLR2 agonist...
2016: PloS One
https://www.readbyqxmd.com/read/26956246/nociceptin-orphanin-fq-receptor-structure-signaling-ligands-functions-and-interactions-with-opioid-systems
#14
REVIEW
Lawrence Toll, Michael R Bruchas, Girolamo Calo', Brian M Cox, Nurulain T Zaveri
The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward...
April 2016: Pharmacological Reviews
https://www.readbyqxmd.com/read/26748051/endomorphin-analog-analgesics-with-reduced-abuse-liability-respiratory-depression-motor-impairment-tolerance-and-glial-activation-relative-to-morphine
#15
James E Zadina, Mark R Nilges, Jenny Morgenweck, Xing Zhang, Laszlo Hackler, Melita B Fasold
Opioids acting at the mu opioid receptor (MOR) are the most effective analgesics, however adverse side effects severely limit their use. Of particular importance, abuse liability results in major medical, societal, and economic problems, respiratory depression is the cause of fatal overdoses, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. Despite the host of negative side effects, opioids such as morphine are commonly used for acute and chronic pain conditions...
June 2016: Neuropharmacology
https://www.readbyqxmd.com/read/26588695/adenosine-a1-receptor-agonist-induced-hyperalgesic-priming-type-ii
#16
Dioneia Araldi, Luiz F Ferrari, Jon D Levine
We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent...
March 2016: Pain
https://www.readbyqxmd.com/read/26483357/safety-of-oral-dronabinol-during-opioid-withdrawal-in-humans
#17
RANDOMIZED CONTROLLED TRIAL
Crystal J Jicha, Michelle R Lofwall, Paul A Nuzzo, Shanna Babalonis, Samy Claude Elayi, Sharon L Walsh
BACKGROUND: Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. METHODS: Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study...
December 1, 2015: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/26451468/inhibition-of-inflammatory-and-neuropathic-pain-by-targeting-a-mu-opioid-receptor-chemokine-receptor5-heteromer-mor-ccr5
#18
Eyup Akgün, Muhammad I Javed, Mary M Lunzer, Michael D Powers, Yuk Y Sham, Yoshikazu Watanabe, Philip S Portoghese
Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i...
November 12, 2015: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26432092/novel-therapies-in-ibs-d-treatment
#19
Judy Nee, Mohammed Zakari, Anthony J Lembo
Irritable bowel syndrome (IBS) is a common gastrointestinal disease characterized by abdominal pain and change in bowel habits. IBS diarrhea predominant (IBS-D), which is arguably the most common subset of IBS, is also associated with rectal urgency, increased frequency, abdominal bloating, and loose to watery stools. Current treatments for diarrhea include mu-opioid agonists (i.e., loperamide, lomotil) and bile acid sequestrants (i.e., cholestyramine) while treatments for abdominal pain include antispasmodics (i...
December 2015: Current Treatment Options in Gastroenterology
https://www.readbyqxmd.com/read/26354917/repeated-mu-opioid-exposure-induces-a-novel-form-of-the-hyperalgesic-priming-model-for-transition-to-chronic-pain
#20
Dioneia Araldi, Luiz F Ferrari, Jon D Levine
The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor...
September 9, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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