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NOP Receptor

Kris Rutten, Wolfgang Schröder, Thomas Christoph, Thomas Koch, Thomas M Tzschentke
Agonists selectively acting at NOP, MOP, DOP and KOP receptors as well as mixed opioid receptor agonists are known to exert anti-hypersensitive efficacy in the rat spinal nerve ligation (SNL) model of neuropathic pain. To investigate the relative contribution of individual opioid receptor activation to the overall efficacy of mixed opioid receptor agonists, selective doses of respective opioid receptor antagonists have to be employed. In order to identify such selective antagonist doses, doses of the selective NOP, MOP, DOP and KOP receptor agonists Ro65-6570, morphine, SNC-80 and U50488H, that produced maximum efficacy without apparent side effects, were challenged by each of the receptor antagonists J-113397 (NOP receptor), naloxone (MOP receptor), naltrindole (DOP receptor) and nor-binaltorphimine (KOP receptor)...
March 7, 2018: European Journal of Pharmacology
Dalibor Milić, Markus Dick, Daniel Mulnaes, Christopher Pfleger, Anna Kinnen, Holger Gohlke, Georg Groth
Synthetic peptides derived from ethylene-insensitive protein 2 (EIN2), a central regulator of ethylene signalling, were recently shown to delay fruit ripening by interrupting protein-protein interactions in the ethylene signalling pathway. Here, we show that the inhibitory peptide NOP-1 binds to the GAF domain of ETR1 - the prototype of the plant ethylene receptor family. Site-directed mutagenesis and computational studies reveal the peptide interaction site and a plausible molecular mechanism for the ripening inhibition...
March 1, 2018: Scientific Reports
Michael Camilleri
This is an editorial summarizing recent new developments in visceral analgesics. This promising field is important as a new approach to address abdominal pain with peripheral visceral analgesics is considered a key approach to addressing the current opioid crisis. Some of the novel compounds address peripheral pain mechanisms through modulation of opioid receptors through biased ligands, nociceptin/orphanin FQ opioid peptide (NOP) receptor or dual action on NOP and μ-opioid receptor, buprenorphine and morphiceptin analogs...
February 22, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
Laura Micheli, Elena Lucarini, Francesca Corti, Roberto Ciccocioppo, Girolamo Calò, Anna Rizzi, Carla Ghelardini, Lorenzo Di Cesare Mannelli
The development of tolerance to the antinociceptive effect is a main problem associated with the repeated administration of opioids. The progressively higher doses required to relieve pain reduce safety and exacerbate the side effects of classical opioid receptor agonists like morphine. Nociceptin/orphanin FQ (N/OFQ) and its NOP receptor constitute the fourth endogenous opioid system that is involved in the control of broad spectrum of biological functions, including pain transmission. Aim of this work was to evaluate the relevance of the N/OFQ-NOP system in morphine antinociceptive action and in the development of morphine tolerance in the rat...
January 26, 2018: European Journal of Pharmacology
Stefano Della Longa, Alessandro Arcovito
Antagonists of the nociceptin receptor (NOP) are raising interest for their possible clinical use as antidepressant drugs. Recently, the structure of NOP in complex with some piperidine-based antagonists has been revealed by X-ray crystallography. In this study, a multi-flexible docking (MF-docking) procedure, i.e. docking to multiple receptor conformations extracted by preliminary molecular dynamics trajectories, together with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have been carried out to provide the binding mode of two novel NOP antagonists, one of them selective (BTRX-246040, formerly named LY-2940094) and one non selective (AT-076), i...
January 16, 2018: Journal of Computer-aided Molecular Design
Carlo Mustazza, Stefano Pieretti, Francesca Marzoli
Nociceptin /Orphanin FQ Peptide" receptor (NOPr) is a G-protein-coupled receptor with the nociceptin/orphanin FQ peptide (N/OFQ) as endogenous agonist. It is expressed in the nervous system as well as in some non-neural tissues. Its activation has pronociceptive effect at the supraspinal level, whereas at the spinal level it produces nociceptive effects at low doses and antinociceptive effects at higher doses. NOPr is also involved in mood and blood pressure regulation, immunoregulation, airway constriction, feeding, urination, bowel motility, learning and memory...
January 10, 2018: Current Medicinal Chemistry
Francesca Felicia Caputi, Elio Acquas, Sanjay Kasture, Stefania Ruiu, Sanzio Candeletti, Patrizia Romualdi
BACKGROUND: Behavioral studies demonstrated that the administration of Withania somnifera Dunal roots extract (WSE), prolongs morphine-elicited analgesia and reduces the development of tolerance to the morphine's analgesic effect; however, little is known about the underpinning molecular mechanism(s). In order to shed light on this issue in the present paper we explored whether WSE promotes alterations of μ (MOP) and nociceptin (NOP) opioid receptors gene expression in neuroblastoma SH-SY5Y cells...
January 10, 2018: BMC Complementary and Alternative Medicine
Ludovico Arcuri, Salvatore Novello, Martina Frassineti, Daniela Mercatelli, Clarissa Anna Pisanò, Ilaria Morella, Stefania Fasano, Blair V Journigan, Michael E Meyer, Willma E Polgar, Riccardo Brambilla, Nurulain T Zaveri, Michele Morari
BACKGROUND AND PURPOSE: We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression. EXPERIMENTAL APPROACH: Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells...
March 2018: British Journal of Pharmacology
Savannah Tollefson, Michael Himes, Rajesh Narendran
Addiction is composed of three phases: intoxication, withdrawal, and craving. Negative reinforcement, strengthening a behaviour by removing an aversive stimulus, has been associated with the withdrawal phase. An imbalance of neurotransmitters within the brain's stress (nociceptin, neuropeptide Y) and anti-stress (CRF, norepinephrine, etc.) system is attributed to negatively reinforced compulsive behaviours associated with relapse. Similarly, post-traumatic stress disorder is characterized by an overactive stress system...
December 2017: International Review of Psychiatry
Nurulain T Zaveri, Paul V Marquez, Michael E Meyer, Willma E Polgar, Abdul Hamid, Kabirullah Lutfy
BACKGROUND: Nociceptin/orphanin FQ, the endogenous peptide agonist for the opioid receptor-like receptor (also known as NOP or the nociceptin receptor), has been shown to block the acquisition and expression of ethanol (EtOH)-induced conditioned place preference (CPP). Here, we report the characterization of a novel small-molecule NOP ligand AT-312 (1-(1-((cis)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol) in receptor binding and GTPγS functional assays in vitro. We then investigated the effect of AT-312 on the rewarding action of EtOH in mice using the CPP paradigm...
February 2018: Alcoholism, Clinical and Experimental Research
Qianwei Shen, Yulin Deng, Roberto Ciccocioppo, Nazzareno Cannella
Cocaine addiction is a widespread psychiatric condition still waiting for approved efficacious medications. Previous studies suggested that simultaneous activation of nociceptin opioid (NOP) and mu opioid (MOP) receptors could be a successful strategy to treat cocaine addiction, but the paucity of molecules co-activating both receptors with comparable potency has hampered this line of research. Cebranopadol is a non-selective opioid agonist that at nanomolar concentration activates both NOP and MOP receptors and that recently reached phase-III clinical trials for cancer pain treatment...
2017: Frontiers in Psychiatry
Thomas M Tzschentke, Kris Rutten
The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism...
February 2018: Neuropharmacology
Abdu Adem, Nather Madjid, Ulrika Kahl, Sarah Holst, Bassem Sadek, Johan Sandin, Lars Terenius, Sven Ove Ögren
The endogenous neuropeptide nociceptin (N/OFQ), which mediates its actions via the nociceptin receptor (NOP), is implicated in multiple behavioural and physiological functions. This study examined the effects of the NOP agonists N/OFQ and the synthetic agonist Ro 64-6198, the antagonists NNN and NalBzoH, as well as deletion of the Pronociceptin gene on emotional memory in mice. The animals were tested in the passive avoidance (PA) task, dependent on hippocampal and amygdala functions. N/OFQ injected intraventricularly (i...
December 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
V Blair Journigan, Willma E Polgar, Edward W Tuan, James Lu, Pankaj R Daga, Nurulain T Zaveri
Few opioid ligands binding to the three classic opioid receptor subtypes, mu, kappa and delta, have high affinity at the fourth opioid receptor, the nociceptin/orphanin FQ receptor (NOP). We recently reported the discovery of AT-076 (1), (R)-7-hydroxy-N-((S)-1-(4-(3-hydroxyphenyl)piperidin-1-yl)-3-methylbutan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, a pan antagonist with nanomolar affinity for all four subtypes. Since AT-076 binds with high affinity at all four subtypes, we conducted a structure-activity relationship (SAR) study to probe ligand recognition features important for pan opioid receptor activity, using chemical modifications of key pharmacophoric groups...
October 16, 2017: Scientific Reports
Anna I Erdei, Adina Borbély, Anna Magyar, Nóra Taricska, András Perczel, Ottó Zsíros, Győző Garab, Edina Szűcs, Ferenc Ötvös, Ferenc Zádor, Mihály Balogh, Mahmoud Al-Khrasani, Sándor Benyhe
In an attempt to design opioid-nociceptin hybrid peptides, three novel bivalent ligands, H-YGGFGGGRYYRIK-NH2, H-YGGFRYYRIK-NH2 and Ac-RYYRIKGGGYGGFL-OH were synthesized and studied by biochemical, pharmacological, biophysical and molecular modelling tools. These chimeric molecules consist of YGGF sequence, a crucial motif in the N-terminus of natural opioid peptides, and Ac-RYYRIK-NH2, which was isolated from a combinatorial peptide library as an antagonist or partial agonist that inhibits the biological activity of the endogenously occurring heptadecapeptide nociceptin...
October 13, 2017: Peptides
Thomas M Tzschentke, Babette Y Kögel, Stefanie Frosch, Klaus Linz
Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ-opioid peptide (MOP) receptors, the present study evaluated opioid-type physical dependence produced by cebranopadol in mice and rats. In a naloxone-precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range...
September 25, 2017: Addiction Biology
Mareike Kessenbrock, Simone M Klein, Lena Müller, Mauricio Hunsche, Georg Noga, Georg Groth
Ethylene signaling is decisive for many plant developmental processes. Among these, control of senescence, abscission and fruit ripening are of fundamental relevance for global agriculture. Consequently, detailed knowledge of the signaling network along with the molecular processes of signal perception and transfer are expected to have high impact on future food production and agriculture. Recent advances in ethylene research have demonstrated that signaling of the plant hormone critically depends on the interaction of the ethylene receptor family with the NRAMP-like membrane protein ETHYLENE INSENSITIVE 2 (EIN2) at the ER membrane, phosphorylation-dependent proteolytic processing of ER-localized EIN2 and subsequent translocation of the cleaved EIN2 C-terminal polypeptide (EIN2-CEND) to the nucleus...
2017: Frontiers in Plant Science
Juliana Almeida da Silva, Audrey Franceschi Biagioni, Rafael Carvalho Almada, Renato Leonardo de Freitas, Norberto Cysne Coimbra
RATIONALE: Gamma-aminobutyric acid (GABA)ergic neurons of the substantia nigra pars reticulata (SNpr) are connected to the deep layers of the superior colliculus (dlSC). The dlSC, in turn, connect with the SNpr through opioid projections. Nociceptin/orphanin FQ peptide (N/OFQ) is a natural ligand of a Gi protein-coupled nociceptin receptor (ORL1; NOP) that is also found in the SNpr. Our hypothesis is that tectonigral opioid pathways and intranigral orphanin-mediated mechanisms modulate GABAergic nigrotectal connections...
October 2017: Psychopharmacology
Federica Ferrari, Davide Malfacini, Blair V Journigan, Mark F Bird, Claudio Trapella, Remo Guerrini, David G Lambert, Girolamo Calo', Nurulain T Zaveri
Nociceptin/orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP), a member of the opioid receptor family. We recently identified a new high affinity and highly selective NOP agonist AT-403. In this study, we characterized the functional profile of AT-403 and compared it to other known nonpeptide NOP agonists Ro 65-6570, Ro 2q, SCH-221510, MCOPPB, AT-202 and SCH-486757, using the following assays: GTPγ[(35) S] stimulated binding, calcium mobilization assay in cells-expressing human NOP or classical opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, and the electrically stimulated mouse vas deferens bioassay...
August 2017: Pharmacology Research & Perspectives
Rajesh Narendran, Roberto Ciccocioppo, Brian Lopresti, Jennifer Paris, Michael L Himes, N Scott Mason
BACKGROUND: The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders...
May 31, 2017: Biological Psychiatry
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