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Novel Mu Agonists

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
Tom H Johnston, Eboo Versi, Patrick A Howson, Paula Ravenscroft, Susan H Fox, Michael P Hill, Bruce E Reidenberg, Ronald Corey, Jonathan M Brotchie
L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki : 0.73 nM); mu antagonist (Ki : 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate...
March 15, 2018: Neuropharmacology
Justyna Piekielna-Ciesielska, Federica Ferrari, Girolamo Calo', Anna Janecka
Opioid peptides and alkaloid drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor which belongs to the G protein-coupled receptor (GPCR) family. A new important pharmacological concept in the field of GPCRs is biased agonism. Two mu receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH2 (C-36) and Dmt-c[D-Lys-Phe-p-CF3 -Phe-Asp]NH2 (F-81), were evaluated in terms of their ability to promote or block mu receptor/G protein and mu receptor/β-arrestin interactions...
March 2018: Peptides
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
Mohamed Farrag, Julie K Drobish, Henry L Puhl, Joyce S Kim, Paul B Herold, Marc P Kaufman, Victor Ruiz-Velasco
KEY POINTS: Chronic limb ischaemia, characterized by inflammatory mediator release and a low extracellular pH, leads to acid-sensing ion channel (ASIC) activation and reflexively increases mean arterial pressure; endomorphin release is also increased under inflammatory conditions. We examined the modulation of ASIC currents by endomorphins in sensory neurons from rats with freely perfused and ligated femoral arteries: peripheral artery disease (PAD) model. Endomorphins potentiated sustained ASIC currents in both groups of dorsal root ganglion neurons, independent of mu opioid receptor stimulation or G protein activation...
December 1, 2017: Journal of Physiology
Ferenc Zádor, Mihály Balogh, András Váradi, Zoltán S Zádori, Kornél Király, Edina Szűcs, Bence Varga, Bernadette Lázár, Sándor Hosztafi, Pál Riba, Sándor Benyhe, Susanna Fürst, Mahmoud Al-Khrasani
14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-O-MeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. The potency and efficacy of test compound were measured by [ 35 S]GTPγS binding, isolated mouse vas deferens (MVD) and rat vas deferens (RVD) assays...
November 5, 2017: European Journal of Pharmacology
Charlotte K Callaghan, Jennifer Rouine, Reginald L Dean, Brian I Knapp, Jean M Bidlack, Daniel R Deaver, Shane M O'Mara
Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, which may be reflective of mechanisms underlying inflammation associated depression...
January 2018: Brain, Behavior, and Immunity
To-Jung Tseng, Ming-Ling Yang, Yu-Lin Hsieh, Miau-Hwa Ko, Sung-Tsang Hsieh
Nerve decompression is an essential therapeutic strategy for pain relief clinically; however, its potential mechanism remains poorly understood. Opioid analgesics acting on opioid receptors (OR) within the various regions of the nervous system have been used widely for pain management. We therefore hypothesized that nerve decompression in a neuropathic pain model of chronic constriction injury (CCI) improves the synaptic OR plasticity in the dorsal horn, which is in response to alleviate pain hypersensitivity...
August 23, 2017: Neurotoxicity Research
Michael H Baumann, Susruta Majumdar, Valerie Le Rouzic, Amanda Hunkele, Rajendra Uprety, Xi Ping Huang, Jin Xu, Bryan L Roth, Ying-Xian Pan, Gavril W Pasternak
Novel synthetic opioids (NSO) are increasingly encountered in illicit heroin and counterfeit pain pills. Many NSO are resurrected from older biomedical literature or patent applications, so limited information is available about their biological effects. Here we examined the pharmacology of three structurally-distinct NSO found in the recreational drug market: N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylbutyramide (butyrylfentanyl), 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and 1-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45)...
August 11, 2017: Neuropharmacology
Joanna Starnowska, Roberto Costante, Karel Guillemyn, Katarzyna Popiolek-Barczyk, Nga N Chung, Carole Lemieux, Attila Keresztes, Joost Van Duppen, Adriano Mollica, John Streicher, Jozef Vanden Broeck, Peter W Schiller, Dirk Tourwé, Joanna Mika, Steven Ballet, Barbara Przewlocka
The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed...
October 18, 2017: ACS Chemical Neuroscience
Yong Zhang, Yupu Liang, Orna Levran, Matthew Randesi, Vadim Yuferov, Connie Zhao, Mary Jeanne Kreek
INTRODUCTION: Non-medical use of prescription opioids such as the mu opioid receptor (MOP-r) agonist oxycodone is a growing problem in the USA and elsewhere. There is limited information about oxycodone's impact on diverse gene systems in the brain. OBJECTIVES: The current study was designed to examine how chronic oxycodone self-administration (SA) affects gene expression in the terminal areas of the nigrostriatal and mesolimbic dopaminergic pathways in mice. METHOD: Adult male C57BL/6J mice underwent a 14-day oxycodone self-administration procedure (4 h/day, 0...
August 2017: Psychopharmacology
S M Kang, J L Rosales, V Meier-Stephenson, S Kim, K Y Lee, A Narendran
L-asparaginase is a critical chemotherapeutic agent for acute lymphoblastic leukemia (ALL). It hydrolyzes plasma asparagine into aspartate and NH3 , causing asparagine deficit and inhibition of protein synthesis and eventually, leukemic cell death. However, patient relapse often occurs due to development of resistance. The molecular mechanism by which ALL cells acquire resistance to L-asparaginase is unknown. Therefore, we sought to identify genes that are involved in L-asparaginase resistance in primary leukemic cells...
October 19, 2017: Oncogene
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
Allison Doyle Brackley, Shayda Sarrami, Ruben Gomez, Kristi A Guerrero, Nathaniel A Jeske
μ-Opioid receptor (MOR) agonists are often used to treat severe pain but can result in adverse side effects. To circumvent systemic side effects, targeting peripheral opioid receptors is an attractive alternative treatment for severe pain. Activation of the δ-opioid receptor (DOR) produces similar analgesia with reduced side effects. However, until primed by inflammation, peripheral DOR is analgesically incompetent, raising interest in the mechanism. We recently identified a novel role for G-protein-coupled receptor kinase 2 (GRK2) that renders DOR analgesically incompetent at the plasma membrane...
May 26, 2017: Journal of Biological Chemistry
Lynn Webster, Jack Henningfield, August R Buchhalter, Suresh Siddhanti, Lin Lu, Aleksandrs Odinecs, Carlo J Di Fonzo, Michael A Eldon
Objective.:  Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design.:  This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting.:  Inpatient clinical research site. Subjects. : Forty-two randomized subjects (73...
March 10, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
Anna Adamska-Bartłomiejczyk, Rossella De Marco, Luca Gentilucci, Alicja Kluczyk, Anna Janecka
The study reports on a series of novel cyclopeptides based on the structure Tyr-[d-Lys-Phe-Phe-Asp]NH2 , a mixed mu and kappa opioid receptor agonist with low nanomolar affinity, in which Phe4 residue was substituted by cyclic amino acids, such as Pro or its six-membered surrogates, piperidine-2-, 3- or 4-carboxylic acids (Pip, Nip and Inp, respectively). All derivatives exhibited high mu- and moderate delta-opioid receptor affinity, and almost no binding to the kappa-opioid receptor. Conformational analysis suggested that the cis conformation of the peptide bond Phe3 -Xaa4 influences receptor selectivity through the control of the position of Phe3 side chain...
April 15, 2017: Bioorganic & Medicinal Chemistry
Benjamin Adam Samuels, Katherine M Nautiyal, Andrew C Kruegel, Marjorie R Levinstein, Valerie M Magalong, Madalee M Gassaway, Steven G Grinnell, Jaena Han, Michael A Ansonoff, John E Pintar, Jonathan A Javitch, Dalibor Sames, René Hen
Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported that tianeptine is a full agonist at the mu opioid receptor (MOR). Here we demonstrate that the acute and chronic antidepressant-like behavioral effects of tianeptine in mice require MOR...
September 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Alessandro Bonifazi, Hideaki Yano, Michael P Ellenberger, Ludovic Muller, Vivek Kumar, Mu-Fa Zou, Ning Sheng Cai, Adrian M Guerrero, Amina S Woods, Lei Shi, Amy Hauck Newman
The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment...
April 13, 2017: Journal of Medicinal Chemistry
Yan Zhou, Rachel Saylor Crowley, Konrad Ben, Thomas E Prisinzano, Mary Jeanne Kreek
Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference...
May 1, 2017: Brain Research
Andrea Bedini, Santi Mario Spampinato
Chronic pain is a clinically relevant and yet unsolved conditions that is poorly treated with the currently available drugs, thus highlighting the urgent need of innovative analgesics. Although opiates are not very effective in the treatment of inflammatory and neuropathic pain, developing novel opioid receptor peptide agonists, as well as modulating the opioid receptor-mediated responses in a ligand-specific fashion, may represent an innovative and promising strategy to identify more efficacious and safer antalgic drugs...
February 15, 2017: Current Medicinal Chemistry
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