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https://www.readbyqxmd.com/read/28419415/allostery-at-opioid-receptors-modulation-with-small-molecule-ligands
#1
REVIEW
Kathryn E Livingston, John R Traynor
Opioid receptors are 7-transmembrane domain receptors that couple to heterotrimeric G proteins. The endogenous ligands for opioid receptors are peptides which bind to the orthosteric site on the receptors. The μ-opioid receptor is the target for opioid analgesics while the δ-opioid receptor has been suggested as a target for pain management, migraine, and depression. Similarly, κ-opioid receptors are involved in pain and depression and nociceptin receptors in pain and mood behaviors. However, exogenous orthosteric ligands for the opioid receptors cause a myriad of on-target side effects...
April 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28378462/targeting-multiple-opioid-receptors-improved-analgesics-with-reduced-side-effects
#2
REVIEW
Thomas Günther, Pooja Dasgupta, Anika Mann, Elke Miess, Andrea Kliewer, Sebastian Fritzwanker, Ralph Steinborn, Stefan Schulz
Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ-opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ-opioid receptor (κ receptor), δ-opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor)...
April 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28376298/addressing-structural-flexibility-at-the-a-ring-on-salvinorin-a-discovery-of-a-potent-kappa-opioid-agonist-with-enhanced-metabolic-stability
#3
Alexander M Sherwood, Rachel Saylor Crowley, Kelly F Paton, Andrew Biggerstaff, Benjamin Neuenswander, Victor W Day, Bronwyn M Kivell, Thomas E Prisinzano
Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a κ-opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone 14, was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50 = 0...
April 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28363796/structure-constrained-endomorphin-analogs-display-differential-antinociceptive-mechanisms-in-mice-after-spinal-administration
#4
Yuan Wang, Jingjing Zhou, Xin Liu, Long Zhao, Zhaojuan Wang, Xianghui Zhang, Kezhou Wang, Linqing Wang, Rui Wang
We previously reported a series of novel endomorphin analogs with unnatural amino acid modifications. These analogs display good binding affinity and functional activity toward the μ opioid receptor (MOP). In the present study, we further investigated the spinal antinociceptive activity of these compounds. The analogs were potent in several nociceptive models. Opioid antagonists and antibodies against several endogenous opioid peptides were used to determine the mechanisms of action of these peptides. Intrathecal pretreatment with naloxone and β-funaltrexamine (β-FNA) effectively inhibited analog-induced analgesia, demonstrating that activity of the analogs is regulated primarily through MOP...
March 29, 2017: Peptides
https://www.readbyqxmd.com/read/28361412/study-of-%C3%AE-and-%C3%AE-opioid-activities-in-agents-with-various-%C3%AE%C2%BA-receptor-selectivity
#5
O Yu Grechko, R A Litvinov, A A Spasov, A I Rashchenko, D M Shtareva, V A Anisimova, V I Minkin
A putative opioid agonist RU-1205 was ineffective within in vitro model of electrically induced contractions of rat ileum assessing the μ- and δ-opioid receptor pathways, while morphine inhibited these contractions in a dose-dependent and naloxone-reversible manners with EC50=2.6×10(-7) M. In vivo experiments revealed no significant effects of RU-1205 on respiration and gastrointestinal tract contractile activity. In contrast, butorphanol decreased respiration rate by 25% (25-100 mg/kg) and slowed down the transit of labeled particles along the small intestine by 77...
March 30, 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28347824/participation-of-dorsal-periaqueductal-gray-5-ht1a-receptors-in-the-panicolytic-like-effect-of-the-%C3%AE%C2%BA-opioid-receptor-antagonist-nor-bni
#6
Jhonatan Christian Maraschin, Camila Biesdorf Almeida, Marcel Pereira Rangel, Camila Marroni Roncon, Caio César Sestile, Hélio Zangrossi, Frederico Guilherme Graeff, Elisabeth Aparecida Audi
Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT1A receptor (5-HT1A-R) is involved in regulating escape behavior that is organized in the dPAG. Activation of κ-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI...
March 24, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28345746/an-analysis-of-errors-discrepancies-and-variation-in-opioid-prescriptions-for-adult-outpatients-at-a-teaching-hospital
#7
Mark C Bicket, Deepa Kattail, Myron Yaster, Christopher L Wu, Peter Pronovost
OBJECTIVE: To determine opioid-prescribing patterns and rate of three types of errors, discrepancies, and variation from ideal practice. DESIGN: Retrospective review of opioid prescriptions processed at an outpatient pharmacy. SETTING: Tertiary institutional medical center. PATIENTS: We examined 510 consecutive opioid medication prescriptions for adult patients processed at an institutional outpatient pharmacy in June 2016 for patient, provider, and prescription characteristics...
January 2017: Journal of Opioid Management
https://www.readbyqxmd.com/read/28339199/structure-based-discovery-of-new-antagonist-and-biased-agonist-chemotypes-for-the-kappa-opioid-receptor
#8
Zhong Zheng, Xi-Ping Huang, Thomas J Mangano, Rodger Zou, Xin Chen, Saheem A Zaidi, Bryan L Roth, Raymond C Stevens, Vsevolod Katritch
The ongoing epidemics of opioid overdose raises an urgent need for effective antiaddiction therapies and addiction-free painkillers. The κ-opioid receptor (KOR) has emerged as a promising target for both indications, raising demand for new chemotypes of KOR antagonists as well as G-protein-biased agonists. We employed the crystal structure of the KOR-JDTic complex and ligand-optimized structural templates to perform virtual screening of available compound libraries for new KOR ligands. The prospective virtual screening campaign yielded a high 32% hit rate, identifying novel fragment-like and lead-like chemotypes of KOR ligands...
April 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28328155/does-dynorphin-play-a-role-in-the-onset-of-puberty-in-female-sheep
#9
J A Lopez, M N Bedenbaugh, R B McCosh, P W Weems, L J Meadows, B Wisman, L M Coolen, R L Goodman, S M Hileman
Puberty onset involves increased gonadotrophin-release (GnRH) release as a result of decreased sensitivity to oestrogen (E2 )-negative feedback. Because GnRH neurones lack E2 receptor α, this pathway must contain interneurones. One likely candidate is KNDy neurones (kisspeptin, neurokinin B, dynorphin). The overarching hypothesis of the present study was that the prepubertal hiatus in luteinising hormone (LH) release involves reduced kisspeptin and/or heightened dynorphin input. We first tested the specific hypothesis that E2 would reduce kisspeptin-immunopositive cell numbers and increase dynorphin-immunopositive cell numbers...
December 2016: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/28326568/early-response-predicts-a-sustained-response-to-eluxadoline-in-patients-with-irritable-bowel-syndrome-with-diarrhoea-in-two-phase-3-studies
#10
W D Chey, L S Dove, D A Andrae, P S Covington
BACKGROUND: The mixed μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, eluxadoline, is licensed in the USA for the treatment of irritable bowel syndrome with diarrhoea (IBS-D), based on the results of two large Phase 3 clinical trials. AIM: To understand the time course of treatment benefits with eluxadoline by comparing responder rates over the first month of treatment with responder rates over longer treatment intervals. METHODS: In this post hoc analysis of two Phase 3 studies, composite and adequate relief (AR) responder rates were calculated over month 1 and patients were stratified by their responder status...
March 22, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28314512/modulation-of-opioid-receptor-affinity-and-efficacy-via-n-substitution-of-9%C3%AE-hydroxy-5-3-hydroxyphenyl-morphan-synthesis-and-computer-simulation-study
#11
Phong M Truong, Sergio A Hassan, Yong-Sok Lee, Theresa A Kopajtic, Jonathan L Katz, Aaron M Chadderdon, John R Traynor, Jeffrey R Deschamps, Arthur E Jacobson, Kenner C Rice
The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ(35)S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(-) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3...
March 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28301473/%C3%AE%C2%BA-opioid-receptor-is-involved-in-the-cardioprotection-induced-by-exercise-training
#12
Xiao Geng, Honglin Zhao, Shumiao Zhang, Juan Li, Fei Tian, Na Feng, Rong Fan, Min Jia, Haitao Guo, Liang Cheng, Jincheng Liu, Wensheng Chen, Jianming Pei
The present study was designed to test the hypothesis that exercise training elicited a cardioprotective effect against ischemia and reperfusion (I/R) via the κ-opioid receptor (κ-OR)-mediated signaling pathway. Rats were randomly divided into four groups: the control group, the moderate intensity exercise (ME) group, the high intensity exercise (HE) group, and the acute exercise (AE) group. For the exercise training protocols, the rats were subjected to one week of adaptive treadmill training, while from the second week, the ME and HE groups were subjected to eight weeks of exercise training, and the AE group was subjected to three days of adaptive treadmill training and one day of vigorous exercise...
2017: PloS One
https://www.readbyqxmd.com/read/28287401/prostaglandin-mediated-inhibition-of-serotonin-signaling-controls-the-affective-component-of-inflammatory-pain
#13
Anand Kumar Singh, Joanna Zajdel, Elahe Mirrasekhian, Nader Almoosawi, Isabell Frisch, Anna M Klawonn, Maarit Jaarola, Michael Fritz, David Engblom
Pain is fundamentally unpleasant and induces a negative affective state. The affective component of pain is mediated by circuits that are distinct from those mediating the sensory-discriminative component. Here, we have investigated the role of prostaglandins in the affective dimension of pain using a rodent pain assay based on conditioned place aversion to formalin injection, an inflammatory noxious stimulus. We found that place aversion induced by inflammatory pain depends on prostaglandin E2 that is synthesized by cyclooxygenase 2 in neural cells...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28277328/isobolographic-analysis-of-drug-combinations-with-intrathecal-brl52537-%C3%AE%C2%BA-opioid-agonist-pregabalin-calcium-channel-modulator-af-353-p2x3-receptor-antagonist-and-a804598-p2x7-receptor-antagonist-in-neuropathic-rats
#14
Young-Hwan Jung, Yeo Ok Kim, Jung Hyun Han, Yong-Chul Kim, Myung Ha Yoon
BACKGROUND: Neuropathic pain should be treated with drug combinations exhibiting multiple analgesic mechanisms of action because the mechanism of neuropathic pain involves multiple physiological causes and is mediated by multiple pathways. In this study, we defined the pharmacological interaction of BRL52537 (κ-opioid agonist), pregabalin (calcium channel modulator), AF 353 (P2X3 receptor antagonist), and A804598 (P2X7 receptor antagonist). METHODS: Animal models of neuropathic pain were established by spinal nerve ligation (SNL) in male Sprague-Dawley rats, and responses to the mechanical stimulation using von Frey filaments were measured...
March 8, 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/28237793/design-synthesis-and-biological-evaluation-of-aminobenzyloxyarylamide-derivatives-as-selective-%C3%AE%C2%BA-opioid-receptor-antagonists
#15
Junwei Wang, Qiao Song, Anhua Xu, Yu Bao, Yungen Xu, Qihua Zhu
Opioid receptors play an important role in both behavioral and mood functions. Based on the structural modification of LY2456302, a series of aminobenzyloxyarylamide derivatives were designed and synthesized as κ opioid receptor antagonists. The κ opioid receptor binding ability of these compounds were evaluated with opioid receptors binding assays. Compounds 1a-d showed high affinity for κ opioid receptor. Especially for compound 1c, exhibited a significant Ki value of 15.7 nM for κ opioid receptor binding and a higher selectivity over μ and δ opioid receptors compared to (±)LY2456302...
April 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28230651/hypoxia-induces-internalization-of-%C3%AE%C2%BA-opioid-receptor
#16
Chunhua Xi, Xuan Liang, Chunhua Chen, Hasan Babazada, Tianzuo Li, Renyu Liu
BACKGROUND: It has been demonstrated that κ-opioid receptor agonists can reduce hypoxia-ischemia brain injury in animal models. However, it is unclear how the κ-opioid receptor responds to hypoxia-ischemia. In the current study, the authors used an in vitro model of oxygen-glucose deprivation and reoxygenation to explore how κ-opioid receptors respond to hypoxia and reoxygenation. METHODS: Mouse neuroblastoma Neuro2A cells were stably transfected with mouse κ-opioid receptor-tdTomato fusion protein or Flag-tagged mouse κ-opioid receptor, divided into several groups (n = 6 to 12), and used to investigate the κ-opioid receptor movement...
May 2017: Anesthesiology
https://www.readbyqxmd.com/read/28230181/dezocine-exhibits-antihypersensitivity-activities-in-neuropathy-through-spinal-%C3%AE-opioid-receptor-activation-and-norepinephrine-reuptake-inhibition
#17
Yong-Xiang Wang, Xiao-Fang Mao, Teng-Fei Li, Nian Gong, Ma-Zhong Zhang
Dezocine is the number one opioid painkiller prescribed and sold in China, occupying 44% of the nation's opioid analgesics market today and far ahead of the gold-standard morphine. We discovered the mechanisms underlying dezocine antihypersensitivity activity and assessed their implications to antihypersensitivity tolerance. Dezocine, given subcutaneously in spinal nerve-ligated neuropathic rats, time- and dose-dependently produced mechanical antiallodynia and thermal antihyperalgesia, significantly increased ipsilateral spinal norepinephrine and serotonin levels, and induced less antiallodynic tolerance than morphine...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28219707/22-azidosalvinorin-a-exhibits-antidepressant-like-effect-in-mice
#18
James Oluwagbamigbe Fajemiroye, Polepally Reddy Prabhakar, Luiz Carlos da Cunha, Elson Alves Costa, Jordan K Zjawiony
The increasing cases of depression has made the searches for new drugs and understanding of the underligning neurobiology of this psychiatric disorder a necessity. Here, we modified the structure of salvinorin A (a known halucinogen) and investigated antidepressant-like activity of its four derivatives; 22-methylsulfanylsalvinorin A(SA1), 2-O-cinnamoylsalvinorin B (CSB), 22-azidosalvinorin A (SA2), and 2-O-(4(')-azidophenylsulfonyl)salvinorin B (SA3). Prior to behavioural tests (Irwin test, open field test - OFT, forced swimming test - FST and tail suspension test - TST), SA1 was prepared by reacting salvinorin B and methylthioacetic acid with 89% yield; CSB was obtained from the reaction of salvinorin B and cinnamic acid with 92% yield; SA2 was obtained from the reaction of salvinorin B and azidoacetic acid with 81% yield; and SA3 was prepared by reacting salvinorin B with 4-azidophenylsulfonyl chloride with 80% yield...
April 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28218838/design-and-synthesis-of-enantiomerically-pure-decahydroquinoxalines-as-potent-and-selective-%C3%AE%C2%BA-opioid-receptor-agonists-with-anti-inflammatory-activity-in-vivo
#19
Michael Soeberdt, Peter Molenveld, Roy P M Storcken, Renaud Bouzanne des Mazery, Geert Jan Sterk, Reshma Autar, Marjon G Bolster, Clemens Wagner, Sebastianus N H Aerts, Frank R van Holst, Anita Wegert, Giovanni Tangherlini, Bastian Frehland, Dirk Schepmann, Dieter Metze, Tobias Lotts, Ulrich Knie, Kun-Yuan Lin, Tai-Yu Huang, Chih-Ching Lai, Sonja Ständer, Bernhard Wünsch, Christoph Abels
In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [(35)S]GTPγS assay, and high selectivity over μ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor...
March 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28216062/nalmefene-reduces-reward-anticipation-in-alcohol-dependence-an-experimental-functional-magnetic-resonance-imaging-study
#20
Darren R Quelch, Inge Mick, John McGonigle, Anna C Ramos, Remy S A Flechais, Mark Bolstridge, Eugenii Rabiner, Matthew B Wall, Rexford D Newbould, Björn Steiniger-Brach, Franz van den Berg, Malcolm Boyce, Dorrit Østergaard Nilausen, Lasse Breuning Sluth, Didier Meulien, Christoph von der Goltz, David Nutt, Anne Lingford-Hughes
BACKGROUND: Nalmefene is a µ- and δ-opioid receptor antagonist, κ-opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol-dependent individuals with "high-risk drinking levels" to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomized, double-blind, placebo-controlled, within-subject crossover design we aimed to determine the effect of a single dose of nalmefene on striatal blood oxygen level-dependent (BOLD) signal change during anticipation of monetary reward using the monetary incentive delay task following alcohol challenge...
January 10, 2017: Biological Psychiatry
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