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https://www.readbyqxmd.com/read/28546566/a-diastereoselective-synthesis-of-cebranopadol-a-novel-analgesic-showing-nop-mu-mixed-agonism
#1
Anna Fantinati, Sara Bianco, Remo Guerrini, Severo Salvadori, Salvatore Pacifico, Maria Camilla Cerlesi, Girolamo Calo, Claudio Trapella
A diastereoselective synthesis of the title compound as a single E diastereomer has been efficiently accomplished by assembling the featured pyrano-indole scaffold of the spiro[cyclohexane-dihydropyrano[3,4-b]-indole]-amine framework through an oxa-Pictet-Spengler reaction, promoted by a cheap and green Zeolite catalyst. Basic pharmacological experiments demonstrate that Cebranopadol acts as a mixed nociception/orphanin FQ (NOP) and mu (MOP) opioid receptor agonist useful for treatment of chronic pain.
May 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28417659/effects-of-nphe-1-arg-14-lys-15-n-ofq-nh2-ufp-101-a-potent-nop-receptor-antagonist-on-molecular-cellular-and-behavioural-alterations-associated-with-chronic-mild-stress
#2
Giovanni Vitale, Monica Filaferro, Maria Vittoria Micioni Di Bonaventura, Valentina Ruggieri, Carlo Cifani, Remo Guerrini, Michele Simonato, Silvia Zucchini
The present study investigated the effect of [Nphe(1)] Arg(14), Lys(15)-N/OFQ-NH2 (UFP-101), a selective NOP receptor antagonist, in chronic mild stress (CMS) in male Wistar rats. NOP receptor antagonists were reported to elicit antidepressant-like effects in rodents. Our aim was to investigate UFP-101 effects on CMS-induced anhedonia and impairment of hippocampal neurogenesis. UFP-101 (10 nmol/rat intracerebroventricularly) did not influence sucrose intake in non-stressed animals, but reinstated basal sucrose consumption in stressed animals from the second week of treatment...
June 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28383520/structure-and-conformation-activity-studies-of-nociceptin-orphanin-fq-receptor-dimeric-ligands
#3
Salvatore Pacifico, Alfonso Carotenuto, Diego Brancaccio, Ettore Novellino, Erika Marzola, Federica Ferrari, Maria Camilla Cerlesi, Claudio Trapella, Delia Preti, Severo Salvadori, Girolamo Calò, Remo Guerrini
The peptide nociceptin/orphanin FQ (N/OFQ) and the N/OFQ receptor (NOP) constitute a neuropeptidergic system that modulates various biological functions and is currently targeted for the generation of innovative drugs. In the present study dimeric NOP receptor ligands with spacers of different lengths were generated using both peptide and non-peptide pharmacophores. The novel compounds (12 peptide and 7 nonpeptide ligands) were pharmacologically investigated in a calcium mobilization assay and in the mouse vas deferens bioassay...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28378462/targeting-multiple-opioid-receptors-improved-analgesics-with-reduced-side-effects
#4
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/28124644/differences-in-innate-immune-response-gene-regulation-in-the-middle-ear-of-children-who-are-otitis-prone-and-in-those-not-otitis-prone
#5
Ravinder Kaur, Janet Casey, Michael Pichichero
OBJECTIVE: Acute otitis media (AOM) causes an inflammatory response in the middle ear. We assessed differences in innate immune responses involved in bacterial defense at onset of AOM in children who were stringently defined as otitis prone (sOP) and children not otitis prone (NOP). STUDY DESIGN: Innate immune genes analysis from middle ear fluid (MEF) samples of children. METHODS: Genes of toll-like receptors (TLR), nod-like and retinoic acid-inducible gene-I-like receptors, downstream effectors important for inflammation and apoptosis, including cytokines and chemokines, were studied from MEF samples by using a real-time polymerase chain reaction array...
November 1, 2016: American Journal of Rhinology & Allergy
https://www.readbyqxmd.com/read/28116100/pharmacological-characterization-of-cebranopadol-a-novel-analgesic-acting-as-mixed-nociceptin-orphanin-fq-and-opioid-receptor-agonist
#6
Anna Rizzi, Maria Camilla Cerlesi, Chiara Ruzza, Davide Malfacini, Federica Ferrari, Sara Bianco, Tommaso Costa, Remo Guerrini, Claudio Trapella, Girolamo Calo'
The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G-proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G-protein and β-arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties...
August 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28112482/antihyperalgesic-antiallodynic-and-antinociceptive-effects-of-cebranopadol-a-novel-potent-nociceptin-orphanin-fq-and-opioid-receptor-agonist-after-peripheral-and-central-administration-in-rodent-models-of-neuropathic-pain
#7
Thomas M Tzschentke, Klaus Linz, Stefanie Frosch, Thomas Christoph
Cebranopadol is a novel and highly potent analgesic acting via nociceptin/orphanin FQ peptide (NOP) and opioid receptors. Since NOP and opioid receptors are expressed in the central nervous system as well as in the periphery, this study addressed the question of where cebranopadol exerts its effects in animal models of chronic neuropathic pain. Mechanical hypersensitivity in streptozotocin (STZ)-treated diabetic rats, cold allodynia in the chronic constriction injury (CCI) model in rats, and heat hyperalgesia and nociception in STZ-treated diabetic and control mice was determined after intraplantar (i...
January 23, 2017: Pain Practice: the Official Journal of World Institute of Pain
https://www.readbyqxmd.com/read/28097008/preclinical-findings-predicting-efficacy-and-side-effect-profile-of-ly2940094-an-antagonist-of-nociceptin-receptors
#8
Jeffrey M Witkin, Linda M Rorick-Kehn, Mark J Benvenga, Benjamin L Adams, Scott D Gleason, Karen M Knitowski, Xia Li, Steven Chaney, Julie F Falcone, Janice W Smith, Julie Foss, Kirsti Lloyd, John T Catlow, David L McKinzie, Kjell A Svensson, Vanessa N Barth, Miguel A Toledo, Nuria Diaz, Celia Lafuente, Alma Jiménez, Alfonso Benito, Conception Pedregal, Maria A Martínez-Grau, Anke Post, Michael A Ansonoff, John E Pintar, Michael A Statnick
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP (-/-) mice...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28000999/n-ofq-system-in-brain-areas-of-nerve-injured-mice-its-role-in-different-aspects-of-neuropathic-pain
#9
M Palmisano, D Mercatelli, F F Caputi, D Carretta, P Romualdi, S Candeletti
Several studies showed that chronic pain causes reorganization and functional alterations of supraspinal brain regions. The nociceptin-NOP receptor system is one of the major systems involved in pain control and much evidence also suggested its implication in stress, anxiety and depression. Therefore, we investigated the nociceptin-NOP system alterations in selected brain regions in a neuropathic pain murine model. Fourteen days after the common sciatic nerve ligature, polymerase chain reaction (PCR) analysis indicated a significant decrease of pronociceptin and NOP receptor mRNA levels in the thalamus; these alterations could contribute to the decrease of the thalamic inhibitory function reported in neuropathic pain condition...
December 21, 2016: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/27871910/pharmacological-studies-on-the-nop-and-opioid-receptor-agonist-pwt2-dmt-1-n-ofq-1-13
#10
Maria Camilla Cerlesi, Huiping Ding, Mark F Bird, Norikazu Kiguchi, Federica Ferrari, Davide Malfacini, Anna Rizzi, Chiara Ruzza, David G Lambert, Mei-Chuan Ko, Girolamo Calo, Remo Guerrini
An innovative chemical strategy named peptide welding technology (PWT) has been developed for the facile synthesis of tetrabranched peptides. [Dmt(1)]N/OFQ(1-13)-NH2 acts as a universal agonist for nociceptin/orphanin FQ (N/OFQ) and classical opioid receptors. The present study investigated the pharmacological profile of the PWT derivative of [Dmt(1)]N/OFQ(1-13)NH2 (PWT2-[Dmt(1)]) in several assays in vitro and in vivo after spinal administration in monkeys subjected to the tail withdrawal assay. PWT2-[Dmt(1)] mimicked the effects of [Dmt(1)]N/OFQ(1-13)-NH2 displaying full agonist activity, similar affinity/potency and selectivity at human recombinant N/OFQ (NOP) and opioid receptors in receptor binding, stimulation of [(35)S]GTPγS binding, calcium mobilization in cells expressing chimeric G proteins, and BRET studies for measuring receptor/G-protein and receptor/β-arrestin 2 interaction...
January 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27793733/post-blast-treatment-with-nociceptin-orphanin-fq-peptide-nop-receptor-antagonist-reduces-brain-injury-induced-hypoxia-and-signaling-proteins-in-vestibulomotor-related-brain-regions
#11
Hibah O Awwad, Cindy D Durand, Larry P Gonzalez, Paul Tompkins, Yong Zhang, Megan R Lerner, Daniel J Brackett, David M Sherry, Vibhudutta Awasthi, Kelly M Standifer
Mild traumatic brain injury (mTBI) diagnoses have increased due to aggressive sports and blast-related injuries, but the cellular mechanisms and pathology underlying mTBI are not completely understood. Previous reports indicate that Nociceptin Orphanin/FQ (N/OFQ), an endogenous neuropeptide, contributes to post-injury ischemia following mechanical brain injury, yet its specific role in cerebral hypoxia, vestibulomotor function and injury marker expression following blast-induced TBI is not known. This study is the first to identify a direct association of N/OFQ and its N/OFQ peptide (NOP) receptor with TBI-induced changes following a single 80psi head blast exposure in male rats...
October 25, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27780725/in-vitro-functional-characterization-of-novel-nociceptin-orphanin-fq-receptor-agonists-in-recombinant-and-native-preparations
#12
Federica Ferrari, Maria Camilla Cerlesi, Davide Malfacini, Laila Asth, Elaine C Gavioli, Blair V Journigan, Uma Gayathri Kamakolanu, Michael E Meyer, Dennis Yasuda, Willma E Polgar, Anna Rizzi, Remo Guerrini, Chiara Ruzza, Nurulain T Zaveri, Girolamo Calo
Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [(35)S]GTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays...
December 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27778406/cebranopadol-novel-dual-opioid-nop-receptor-agonist-analgesic
#13
REVIEW
R B Raffa, G Burdge, J Gambrah, H E Kinecki, F Lin, B Lu, J T Nguyen, V Phan, A Ruan, M A Sesay, T N Watkins
WHAT IS KNOWN AND OBJECTIVE: Chronic pain presents a difficult clinical challenge because of the limited efficacy, the limiting adverse-effect profile or the abuse potential of current analgesic options. Cebranopadol is a novel new agent in clinical trials that combines dual agonist action at opioid and nociceptin/orphanin FQ peptide (NOP) receptors. It is the first truly unique, centrally acting analgesic in several years. We here review the basic and clinical pharmacology of cebranopadol...
February 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/27751964/altered-expression-of-glial-markers-chemokines-and-opioid-receptors-in-the-spinal-cord-of-type-2-diabetic-monkeys
#14
Norikazu Kiguchi, Huiping Ding, Christopher M Peters, Nancy D Kock, Shiroh Kishioka, J Mark Cline, Janice D Wagner, Mei-Chuan Ko
Neuroinflammation is a pathological condition that underlies diabetes and affects sensory processing. Given the high prevalence of pain in diabetic patients and crosstalk between chemokines and opioids, it is pivotal to know whether neuroinflammation-associated mediators are dysregulated in the central nervous system of diabetic primates. Therefore, the aim of this study was to investigate whether mRNA expression levels of glial markers, chemokines, and opioid receptors are altered in the spinal cord and thalamus of naturally occurring type 2 diabetic monkeys (n=7) compared with age-matched non-diabetic monkeys (n=6)...
January 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27667485/functional-pharmacological-characterisation-of-ser100-in-cardiovascular-health-and-disease
#15
Inmaculada C Villar, Kristen J Bubb, Amie J Moyes, Eva Steiness, Trygve Gulbrandsen, Finn Olav Levy, Adrian J Hobbs
BACKGROUND AND PURPOSE: SER100 is a selective nociceptin receptor (NOP) agonist with sodium-potassium-sparing aquaretic and anti-natriuretic activity. This study was designed to characterize the functional cardiovascular pharmacology of SER100 in vitro and in vivo, including experimental models of cardiovascular disease. EXPERIMENTAL APPROACH: Haemodynamic, ECG parameters and heart rate variability (HRV) were determined using radiotelemetry in healthy, conscious mice...
September 25, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27573832/a-novel-orvinol-analog-bu08028-as-a-safe-opioid-analgesic-without-abuse-liability-in-primates
#16
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/27562660/nociceptin-reduces-the-inflammatory-immune-microenvironment-in-a-conventional-murine-model-of-airway-hyperresponsiveness
#17
G Spaziano, R Sorrentino, M Matteis, G Malgieri, M Sgambato, T P Russo, M Terlizzi, F Roviezzo, F Rossi, A Pinto, R Fattorusso, B D'Agostino
BACKGROUND: Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are involved in airway hyperresponsiveness (AHR) and inflammation. However, the role of nociceptin at modulating the inflammatory immune microenvironment in asthma is still unclear. OBJECTIVE: To understand the role of N/OFQ in the regulation of a Th2-like environment, we used a conventional murine model of AHR. METHODS: Balb/c and CD1 mice were sensitized to ovalbumin (OVA) and treated with saline solution or N/OFQ, at days 0 and 7...
October 5, 2016: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27562376/genetic-deletion-of-the-nociceptin-orphanin-fq-receptor-in-the-rat-confers-resilience-to-the-development-of-drug-addiction
#18
Marsida Kallupi, Giulia Scuppa, Giordano de Guglielmo, Girolamo Calò, Friedbert Weiss, Michael A Statnick, Linda M Rorick-Kehn, Roberto Ciccocioppo
The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (-/-) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0...
February 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27515665/the-nociceptin-orphanin-fq-receptor-agonist-sr-8993-as-a-candidate-therapeutic-for-alcohol-use-disorders-validation-in-rat-models
#19
Abdul Maruf Asif Aziz, Shaun Brothers, Gregory Sartor, Lovisa Holm, Markus Heilig, Claes Wahlestedt, Annika Thorsell
RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats...
October 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27371029/changes-in-nociceptin-orphanin-fq-levels-in-rat-brain-regions-after-acute-and-chronic-cannabinoid-treatment-in-conjunction-with-the-development-of-antinociceptive-tolerance
#20
Ahmet Ulugol, Ruhan D Topuz, Ozgur Gunduz, Gulnur Kizilay, Hakan C Karadag
It has been indicated that acute and chronic morphine administrations enhance nociceptin/orphanin FQ (N/OFQ) levels in the brain, which might play role in the development of tolerance to the antinociceptive effect of morphine. Accordingly, N/OFQ receptor (NOP) antagonists have been shown to prevent the development of antinociceptive tolerance to morphine. Our aim is to observe whether cannabinoids, similarly to opioids, enhance N/OFQ levels in pain-related brain regions and whether antagonism of NOP receptors attenuates the development of tolerance to the antinociceptive effect of cannabinoids...
December 2016: Fundamental & Clinical Pharmacology
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