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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/28377055/original-endomorphin-1-analogues-exhibit-good-analgesic-effects-with-minimal-implications-for-human-sperm-motility
#3
Yiqing Wang, Xinyi Zhao, Xuelin Gao, Yongan Gan, Ying Liu, Xiaodong Zhao, Junping Hu, Xiaoling Ma, Yanjing Wu, Pengcheng Ma, Xiaolei Liang, Xuehong Zhang
To search a novel analgesic characterizes the effects on human sperm motility as minimal as possible. A new class of endomorphin-1 (EM-1) analogues was synthesized by combining successful chemical modifications including N-terminal guanidino modification, Phe(4) was chlorinated, replaced of l-Pro(2)-Trp(3) by d-Ala(2)-Gly(3) or d-Pro(2)-Gly(3) at position 2 and 3. Their bioactivities were measured by radioligand binding assay, metabolic stability, antinociception activity and sperm motility effects. In radioligand binding assays, analogue GAGP shown a μ-opioid receptor affinity about 17...
March 27, 2017: Bioorganic & Medicinal Chemistry Letters
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
#4
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/28368122/synthesis-and-evaluation-of-a-64-cu-conjugate-a-selective-%C3%AE-opioid-receptor-positron-emission-tomography-imaging-agent
#5
Azadeh Pirisedigh, Véronique Blais, Samia Ait-Mohand, Khaled Abdallah, Brian J Holleran, Richard Leduc, Yves L Dory, Louis Gendron, Brigitte Guérin
Given the putative selectivity of the antagonist TIPP (Tyr-Tic-Phe-Phe) for δ-opioid receptors (DOP), this compound was selected for the design of a novel (64)Cu-radiolabeled potent and selective DOP positron emission tomography (PET) imaging agent. Ex vivo autoradiography of TIPPD-PEG-K(NOTA/(64)Cu)-NH2 on rat brain sections produced a distribution pattern consistent with the known expression of DOP. Taken together, the in vitro and ex vivo data indicate that this (64)Cu-tracer holds promise for studying the DOP by means of PET...
April 3, 2017: Organic Letters
https://www.readbyqxmd.com/read/28363796/structure-constrained-endomorphin-analogs-display-differential-antinociceptive-mechanisms-in-mice-after-spinal-administration
#6
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
#7
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/28327612/endogenous-opioids-regulate-moment-to-moment-neuronal-communication-and-excitability
#8
Bryony L Winters, Gabrielle C Gregoriou, Sarah A Kissiwaa, Oliver A Wells, Danashi I Medagoda, Sam M Hermes, Neil T Burford, Andrew Alt, Sue A Aicher, Elena E Bagley
Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability...
March 22, 2017: Nature Communications
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
#9
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/28322978/delta-opioid-receptor-antagonism-leads-to-excessive-ethanol-consumption-in-mice-with-enhanced-activity-of-the-endogenous-opioid-system
#10
Piotr Poznanski, Anna Lesniak, Michal Korostynski, Klaudia Szklarczyk, Marzena Lazarczyk, Piotr Religa, Magdalena Bujalska-Zadrozny, Bogdan Sadowski, Mariusz Sacharczuk
The opioid system modulates the central reinforcing effects of ethanol and participates in the etiology of addiction. However, the pharmacotherapy of ethanol dependence targeted on the opioid system is little effective and varies due to individual patients' sensitivity. In the present study, we used two mouse lines with high (HA) and low (LA) activity of the endogenous opioid system to analyze the effect of opioid receptor blockade on ethanol drinking behavior. We found that LA and HA lines characterized by divergent magnitudes of swim stress-induced analgesia also differ in ethanol intake and preference...
March 18, 2017: Neuropharmacology
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/28296145/synthesis-and-opioid-activity-of-tyr-1-%C3%AF-z-cf-ch-gly-2-and-tyr-1-%C3%AF-s-r-cf3-ch-nh-gly-2-leu-enkephalin-fluorinated-peptidomimetics
#12
Somnath Narayan Karad, Mohan Pal, Rachel S Crowley, Thomas E Prisinzano, Ryan A Altman
We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr(1) -ψ[(Z)CF=CH]-Gly(2) ) and trifluoroethylamine (Tyr(1) -ψ[(S)/(R)-CF3 CH-NH]-Gly(2) ) analogues of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exhibited low nanomolar functional activity (5.0±2 nm and 60±15 nm for δ- and μ-opioid receptors, respectively) with a μ/δ-selectivity ratio that mimics that of the natural peptide. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position...
March 14, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28291693/synthesis-and-evaluation-of-a-ligand-targeting-the-%C3%AE-and-%C3%AE-opioid-receptors-for-drug-delivery-to-lung-cancer
#13
Guo Li, Philip S Low
A well-established approach to developing new imaging agents and treatments for cancer begins with the recognition of receptors that are overexpressed in cancer cells. Ideally, these same receptors would also be absent, or minimally expressed, in healthy tissue. The mu (μ) and delta (δ) opioid receptors (MOR and DOR respectively) match these criteria, with expression in cancer cells that is higher than primary lung epithelial cells. Naltrexone is a drug approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence or prevention of relapse from opioid addiction...
May 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28276811/new-therapeutic-options-for-ibs-the-role-of-the-first-in-class-mixed-%C3%A2%C2%B5-opioid-receptor-agonist-and-%C3%AE-opioid-receptor-antagonist-mudelta-eluxadoline
#14
Maura Corsetti, Peter Whorwell
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder which represents a major cost to healthcare services. IBS-D patients represent about one-third of the IBS population and are currently treated with antispasmodics, loperamide, bile acid sequestrants and antidepressants. Alosetron and rifaximin are also available in USA, ramosetron in Japan, Korea and Thailand and ondansetron as an off-label treatment. Areas covered: This article focuses on eluxadoline, a novel pharmacological agent that has recently been approved by both the FDA and EMA for treatment of patients with IBS-D...
April 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28274721/role-of-%C3%AE-endorphin-in-pain-relief-following-high-rate-repetitive-transcranial-magnetic-stimulation-in-migraine
#15
Usha Kant Misra, Jayantee Kalita, Gyanesh Tripathi, Sanjeev Kumar Bhoi
BACKGROUND: In migraine, high rate repetitive transcranial magnetic stimulation (rTMS) has been reported to be effective, and β endorphin (BE) may have a role in headache relief. OBJECTIVE: To report the role of BE and its μ (MOR) and δ opioid receptors (DOR) in headache relief following high rate rTMS in migraine. METHODS: Ninety-three migraine patients having more than 4 attacks per month were included. 10 Hz rTMS (600 pulses in 10 trains) was delivered to left motor cortex; 3 sessions to 24 (group 1), 1 session to 22 (group II) and sham stimulation to 47 patients (group III)...
February 24, 2017: Brain Stimulation
https://www.readbyqxmd.com/read/28256374/original-endomorphin-1-analogues-exhibit-good-analgesic-effects
#16
Yanjing Wu, Xinyi Zhao, Yongan Gan, Xuehong Zhang, Hongbin Wei, Lewei Wang, Xiaolei Liang, Xuelin Gao, Ying Liu, Junping Hu, Yiqing Wang
A new class of endomorphin-1 analogues was synthesized by combining successful chemical modifications including N-terminal guanidino modification, Phe(4) was chlorinated, D-Ala-Gly Substituted L-Pro(2). Their bioactivities were measured by radioligand binding assay, metabolic stability and the tail-flick test. In radioligand binding assays, analogue GAGPC (N(α)-Amidino-Tyr-D-Ala-Gly-Trp-p-Cl-Phe-NH2), shown a μ-opioid receptor affinity about 1.42-fold higher and a 2.51-fold higher δ-opioid receptor affinity than EM-1...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28237793/design-synthesis-and-biological-evaluation-of-aminobenzyloxyarylamide-derivatives-as-selective-%C3%AE%C2%BA-opioid-receptor-antagonists
#17
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/28230181/dezocine-exhibits-antihypersensitivity-activities-in-neuropathy-through-spinal-%C3%AE-opioid-receptor-activation-and-norepinephrine-reuptake-inhibition
#18
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/28219718/a-novel-regulatory-role-of-rgs4-in-stat5b-activation-neurite-outgrowth-and-neuronal-differentiation
#19
Paschalina Pallaki, Eirini-Maria Georganta, Ioannis Serafimidis, Maria-Pagona Papakonstantinou, Vassilis Papanikolaou, Sofia Koutloglou, Elsa Papadimitriou, Adamantia Agalou, Aggeliki Tserga, Alexandra Simeonof, Dimitra Thomaidou, Maria Gaitanou, Zafiroula Georgoussi
The Regulator of G protein Signalling 4 (RGS4) is a multitask protein that interacts with and negatively modulates opioid receptor signalling. Previously, we showed that the δ-opioid receptor (δ-OR) forms a multiprotein signalling complex consisting of Gi/Go proteins and the Signal Transducer and Activator of Transcription 5B (STAT5B) that leads to neuronal differentiation and neurite outgrowth upon δ-ΟR activation. Here, we investigated whether RGS4 could participate in signalling pathways to regulate neurotropic events...
February 17, 2017: Neuropharmacology
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
#20
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
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