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https://www.readbyqxmd.com/read/28522254/novel-delta-opioid-receptor-agonists-with-oxazatricyclodecane-structure-showing-potent-agonistic-activities
#1
Kohei Hayashida, Shigeto Hirayama, Takashi Iwai, Yoshikazu Watanabe, Toshihiro Takahashi, Junichi Sakai, Eriko Nakata, Tomio Yamakawa, Hideaki Fujii, Hiroshi Nagase
We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR...
April 19, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28493170/eluxadoline-a-review-in-diarrhoea-predominant-irritable-bowel-syndrome
#2
Gillian M Keating
Eluxadoline (Truberzi(®)) is an orally administered, minimally absorbed agent that acts locally in the gastrointestinal tract as a mixed µ-opioid receptor agonist and δ-opioid receptor antagonist. The randomized, double-blind, placebo-controlled, multinational, phase 3 IBS-3001 and IBS-3002 trials examined the efficacy of eluxadoline in patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). The composite response rate (i.e. the proportion of patients with improvement in both worst abdominal pain and stool consistency on ≥50% of days; primary endpoint), was significantly higher in patients receiving eluxadoline 100 mg twice daily than in those receiving placebo after 12 and 26 weeks' therapy...
June 2017: Drugs
https://www.readbyqxmd.com/read/28489639/evaluation-of-analgesia-tolerance-and-the-mechanism-of-action-of-morphine-6-o-sulfate-across-multiple-pain-modalities-in-sprague-dawley-rats
#3
Jai Shankar K Yadlapalli, Navdeep Dogra, Anqi W Walbaum, William D Wessinger, Paul L Prather, Peter A Crooks, Maxim Dobretsov
BACKGROUND: Morphine-6-O-sulfate (M6S) is a mixed μ/δ-opioid receptor (OR) agonist and potential alternative to morphine for treatment of chronic multimodal pain. METHODS: To provide more support for this hypothesis, the antinociceptive effects of M6S and morphine were compared in tests that access a range of pain modalities, including hot plate threshold (HPT), pinprick sensitivity threshold (PST) and paw pressure threshold tests. RESULTS: Acutely, M6S was 2- to 3-fold more potent than morphine in HPT and PST tests, specifically, derived from best-fit analysis of dose-response relationships of morphine/M6S half-effective dose (ED50) ratios (lower, upper 95% confidence interval [CI]) were 2...
May 4, 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/28485408/genetic-and-pharmacological-antagonism-of-nk1-receptor-prevents-opiate-abuse-potential
#4
A J Sandweiss, M I McIntosh, A Moutal, R Davidson-Knapp, J Hu, A K Giri, T Yamamoto, V J Hruby, R Khanna, T M Largent-Milnes, T W Vanderah
Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1R) in the VTA renders morphine non-rewarding...
May 9, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28455226/the-effect-of-selective-opioid-receptor-agonists-and-antagonists-on-epileptiform-activity-in-morphine-dependent-infant-mice-hippocampal-slices
#5
Yousef Panahi, Ehsan Saboory, Ali Rassouli, Goudarz Sadeghi-Hashjin, Shiva Roshan-Milani, Leila Derafshpour, Yousef Rasmi
Hippocampal slices of mouse brain were used to estimate how selective agonist and antagonist of opioid receptors alter Low-Mg(+2) artificial cerebrospinal fluid (LM-ACSF)-induced epileptiform activities in normal and morphine-dependent mice. Brain slices were obtained from control and morphine-dependent mice. The morphine-dependent group received morphine once a day for 5 consecutive days, and the control group received saline. All injections were administered subcutaneously (s.c) in a volume of 0.1mL on postnatal days 14-18...
April 25, 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28435535/opioid-receptor-activity-and-analgesic-potency-of-dpdpe-peptide-analogues-containing-a-xylene-bridge
#6
Azzurra Stefanucci, Ettore Novellino, Sako Mirzaie, Giorgia Macedonio, Stefano Pieretti, Paola Minosi, Edina Szűcs, Anna I Erdei, Ferenc Zádor, Sándor Benyhe, Adriano Mollica
d-Pen(2),d-Pen(5) enkephalin (DPDPE) is one of the most selective synthetic peptide agonists targeting the δ-opioid receptor. Three cyclic analogues of DPDPE containing a xylene bridge in place of disulfide bond have been synthesized and fully characterized as opioid receptors agonists. The in vitro activity was investigated showing a good affinity of 7a-c for μ- and δ-receptors. In vivo biological assays revealed that 7b is the most potent analogue with the ability to maintain high level of analgesia from 15 to 60 min following intracerebroventricular (i...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28419415/allostery-at-opioid-receptors-modulation-with-small-molecule-ligands
#7
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
#8
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
#9
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/28368122/synthesis-and-evaluation-of-a-64-cu-conjugate-a-selective-%C3%AE-opioid-receptor-positron-emission-tomography-imaging-agent
#10
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
#11
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...
May 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
#12
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
#13
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
#14
RANDOMIZED CONTROLLED TRIAL
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...
May 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
#15
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...
May 15, 2017: Neuropharmacology
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
#16
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
#17
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
#18
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)...
May 2017: Brain Stimulation
https://www.readbyqxmd.com/read/28256374/original-endomorphin-1-analogues-exhibit-good-analgesic-effects
#19
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
#20
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
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