Review
Biochemistry & Molecular Biology
Amal El Daibani, Tao Che
Summary: In our society today, pain has become a significant source of strain on individuals. Developing new pain treatments with fewer adverse effects is crucial. The NOP receptor has emerged as a promising focal point for novel pain therapies, offering an alternative to opioid morphine with potential life-threatening effects and addiction. This article reviews the molecular and cellular structure controlling the cellular trafficking of the NOP receptor and presents studies supporting its role in pain management.
Review
Biochemistry & Molecular Biology
Massimo Ubaldi, Nazzareno Cannella, Anna Maria Borruto, Michele Petrella, Maria Vittoria Micioni Di Bonaventura, Laura Soverchia, Serena Stopponi, Friedbert Weiss, Carlo Cifani, Roberto Ciccocioppo
Summary: Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide that binds the NOP receptor and exerts anti-opioids effects; the NOP receptor is widely expressed in the brain, while N/OFQ is mainly localized in stress-related brain nuclei; preclinical evidence suggests that both NOP agonists and antagonists may be effective therapeutic approaches for substance use disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Mark F. Bird, Christopher P. Hebbes, Anushuya Tamang, Jonathon Mark Willets, Jonathan P. Thompson, Remo Guerrini, Girolamo Calo, David G. Lambert
Summary: In this study, the role of N/OFQ-NOP system was explored in freshly isolated volunteer human B- and T-cells incubated with LPS and PepG as a model of in vitro sepsis. The findings suggest that N/OFQ-NOP receptors play a regulatory role in B and T cell function, inhibiting cell migration and reducing GM-CSF release to variable degrees.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Omar N. Al Yacoub, Hibah O. Awwad, Yong Zhang, Kelly M. Standifer
Summary: This article reviews the role of the N/OFQ-NOP receptor system in the neurological and behavioral sequelae of PTSD and TBI. The current findings suggest that NOP modulators may have potential as therapeutics for these disorders and their co-morbidities. The authors advocate for the development of standards for common data elements reporting to improve reproducibility and data sharing.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Elaine C. Gavioli, Victor A. D. Holanda, Girolamo Calo, Chiara Ruzza
Summary: Resilience plays a crucial role in mental health, and understanding its mechanisms can improve treatment outcomes and help high-risk individuals. The N/OFQ-NOP system is central to stress response, affecting hormone secretion, behavior, and psychopathologies.
Article
Pharmacology & Pharmacy
Sonny H. J. Sliepen, Johanna Korioth, Thomas Christoph, Thomas M. Tzschentke, Marta Diaz-delCastillo, Anne-Marie Heegaard, Kris Rutten
Summary: This study investigated the analgesic potential of NOP receptor activation in a rodent cancer-induced bone pain model, finding that Nociceptin and Ro65-6570 could inhibit cancer-induced mechanical allodynia, with J-113397 selectively antagonizing the effect of Ro65-6570. Additionally, MRMT-1/Luc2-bearing animals showed elevated plasma cytokine levels and altered expression of NOP-r gene in DRG and bone marrow.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Ian B. Denys, Juan Gao, Jane C. Sutphen, Nurulain T. Zaveri, Daniel R. Kapusta
Summary: The study demonstrates that nonpeptide NOP agonists decrease blood pressure and produce diuresis, with AT-039 being a novel nonpeptide NOP agonist that lacks sedative and hyperphagic effects, making it potentially useful in the treatment of hypertension and/or volume overload/hyponatremia.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Stephen R. Morairty, Yu Sun, Lawrence Toll, Michael R. Bruchas, Thomas S. Kilduff
Summary: This study evaluated the effects of two NOPR agonists on sleep/wake in rats, mice, and Cynomolgus macaques. The results showed that these agonists increased non-Rapid Eye Movement sleep and electroencephalogram slow wave activity, while suppressing Rapid Eye Movement sleep in all three species. These findings suggest that the N/OFQ-NOPR system may have a previously unrecognized role in sleep/wake control and could be a potential therapeutic target for insomnia.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Neurosciences
Sarah Sayers, Nikki Le, Jennifer Hernandez, Veronica Mata-Pacheco, Edward J. Wagner
Summary: N/OFQ(ARC) neurons play a vital role in promoting rebound hyperphagia by inhibiting anorexigenic neural substrates under negative energy balance conditions, an effect that is diminished by E-2 in females.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Chemistry, Medicinal
Salvatore Pacifico, Valentina Albanese, Davide Illuminati, Erika Marzola, Martina Fabbri, Federica Ferrari, Victor A. D. Holanda, Chiara Sturaro, Davide Malfacini, Chiara Ruzza, Claudio Trapella, Delia Preti, Ettore Lo Cascio, Alessandro Arcovito, Stefano Della Longa, Martina Marangoni, Davide Fattori, Romina Nassini, Girolamo Calo, Remo Guerrini
Summary: In this study, 31 peptides were synthesized and tested for their activity at human recombinant NOP/opioid receptors. The peptide [Dmt(1,5)]N/OFQ(1-13)-NH2 was identified as the most potent dual NOP/mu receptor agonist, with antitussive effects demonstrated in vivo. The molecular mechanisms of peptide binding to the mu receptor were elucidated through experimental and in silico studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Omar N. Al Yacoub, Stefano Tarantini, Yong Zhang, Anna Csiszar, Kelly M. Standifer
Summary: Traumatic brain injury (TBI) affects millions of people each year and is a leading cause of death and disability. This study suggests that the N/OFQ-NOP receptor pathway plays a significant role in regulating cerebral blood flow and injury markers in TBI, indicating that the NOP receptor could be a potential therapeutic target for TBI.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Ana Domi, Veronica Lunerti, Michele Petrella, Esi Domi, Anna Maria Borruto, Massimo Ubaldi, Friedbert Weiss, Roberto Ciccocioppo
Summary: Genetic deletion or pharmacological blockade of NOP receptors have shown to reduce nicotine intake and motivation to self-administer in rats. The NOP receptor antagonist LY2817412 decreased nicotine intake in wild-type rats, confirming its effect is mediated by inhibition of NOP transmission. Injection of LY2817412 into the VTA decreased nicotine self-administration, suggesting that NOP receptor antagonism may be a potential treatment for smoking cessation.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Psychiatry
Fangmin Wang, Wenwen Shen, Yujia Cai, Xin Zhang, Han Du, Miaojun Lai, Huifen Liu, Evelyne Kohli, Wenhua Zhou
Summary: Buprenorphine can reduce METH intake and drug-seeking behavior by activating NOP receptors.
FRONTIERS IN PSYCHIATRY
(2022)
Article
Geriatrics & Gerontology
Marco Raffaele, Kristina Kovacovicova, Tommaso Biagini, Oriana Lo Re, Jan Frohlich, Sebastiano Giallongo, James D. Nhan, Antonino Giulio Giannone, Daniela Cabibi, Martin Ivanov, Anton B. Tonchev, Martin Mistrik, Matthew Lacey, Petr Dzubak, Sona Gurska, Marian Hajduch, Jiri Bartek, Tommaso Mazza, Vincenzo Micale, Sean P. Curran, Manlio Vinciguerra
Summary: The study identified MCOPB as a NOP ligand with tissue-specific senolytic effects, reducing the senescent cell burden in peripheral tissues but not affecting the central nervous system. Additionally, exposure to MCOPB led to changes in locomotion and lipid storage. Mechanistically, MCOPB treatment activated transcriptional networks involved in immune responses to external stressors, implicating Toll-like receptors (TLRs).
Review
Pharmacology & Pharmacy
Huiping Ding, Norikazu Kiguchi, MaryBeth Dobbins, E. Alfonso Romero-Sandoval, Shiroh Kishioka, Mei-Chuan Ko
Summary: As currently available opioid analgesics often have dose-limiting adverse effects, new approaches have been pursued to develop safe and non-addictive pain medications. NOP receptor-related agonists have emerged as a promising target for developing novel opioids that modulate the analgesic and addictive properties of MOP receptor agonists. Several lines of evidence suggest that peptidic and non-peptidic NOP receptor agonists and mixed NOP/MOP receptor partial agonists show potent analgesic effects in experimental animal models without eliciting adverse effects.
Article
Biochemistry & Molecular Biology
Alessandro Bonardi, Silvia Bua, Jacob Combs, Carrie Lomelino, Jacob Andring, Sameh Mohamed Osman, Alessandra Toti, Lorenzo Di Cesare Mannelli, Paola Gratteri, Carla Ghelardini, Robert McKenna, Alessio Nocentini, Claudiu T. Supuran
Summary: Human carbonic anhydrase isoforms IX and XII have been confirmed as anticancer targets, with three-tails approach showing higher selectivity against tumor-associated isoforms and demonstrating anti-proliferative effects in various cancer cell lines. X-ray crystallography studies have been conducted to investigate the binding mode of these inhibitors, providing valuable insights for potential cancer treatments.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Elisabetta Coppi, Federica Cherchi, Martina Venturini, Elena Lucarini, Renato Corradetti, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Felicita Pedata, Anna Maria Pugliese
Summary: This review summarizes the effects of the latest generation of A(3)R ligands, which have not yet been commercially available, on central and peripheral nervous system diseases. It focuses on the potential therapeutic effects of these ligands, particularly in the treatment of brain ischemia and colitis.
Article
Chemistry, Medicinal
Lara Testai, Eleonora Pagnotta, Eugenia Piragine, Lorenzo Flori, Valentina Citi, Alma Martelli, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Roberto Matteo, Serafino Suriano, Antonio Troccoli, Nicola Pecchioni, Vincenzo Calderone
Summary: This study demonstrates that Eruca sativa DSM extract has beneficial nutraceutical properties on the cardiovascular system, mainly attributed to its ability to release H2S.
PHYTOTHERAPY RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Tiziano De Ventura, Mariasole Perrone, Sonia Missiroli, Paolo Pinton, Paolo Marchetti, Giovanni Strazzabosco, Giulia Turrin, Davide Illuminati, Virginia Cristofori, Anna Fantinati, Martina Fabbri, Carlotta Giorgi, Claudio Trapella, Vinicio Zanirato
Summary: A new chalconoid, velutone F, from the Millettia velutina plant, has shown potent effects as an NLRP3-inflammasome inhibitor; the search for new NLRP3 inhibitors is a current topic of interest in medicinal chemistry. Researchers have reported the synthesis of velutone F and unknown non-natural regioisomers using different synthetic strategies, providing a useful pathway for further studies on NLRP3-inhibitors in the flavonoid class.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Nutrition & Dietetics
Latha Nagamani Dilliraj, Giovanna Schiuma, Djidjell Lara, Giovanni Strazzabosco, James Clement, PierPaolo Giovannini, Claudio Trapella, Marco Narducci, Roberta Rizzo
Summary: Ketone bodies are small compounds derived from fatty acids that serve as an alternative energy source when insulin levels are low. Apart from their metabolic function, ketone bodies also have signaling functions and potential impacts on clinical conditions. This article reviews current data on ketone bodies in relation to nutrition, metabolic pathways, signaling functions, and potential clinical implications. However, more studies, including clinical trials, are needed to confirm the findings and examine the systemic and metabolic consequences of ketone bodies.
Article
Medicine, General & Internal
Simone Fantoni, Ilenia Gabucci, Paolo Cardarelli, Gianfranco Paterno, Angelo Taibi, Virginia Cristofori, Claudio Trapella, Armando Bazzani, Marta Assenza, Alice Zanna Bonacorsi, Daniele Conti, Fabio Baruffaldi
Summary: This study assessed a new cationic contrast agent, CA4+, in the spatial distribution and saturation time in bovine cartilage. The results showed that CA4+ was distributed in three distinct layers in the cartilage and had a longer saturation time. Clinical CT results confirmed the contrast enhancement effect of CA4+ in the cartilage, with different regions showing different degrees of contrast enhancement. In addition, partial washout of the cartilage was observed.
Article
Chemistry, Medicinal
Laura Micheli, Valentina Maggini, Clara Ciampi, Eugenia Gallo, Patrizia Bogani, Renato Fani, Luisa Pistelli, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Marinella De Leo, Fabio Firenzuoli
Summary: Chemotherapy-induced neuropathy is a major side effect of anticancer drugs, causing chronic pain and reduced quality of life. Echinacea extracts (EP4-R-E and EP4-R-BU) showed potential in treating oxaliplatin-induced neuropathic pain. EP4-R-E exerted anti-hyperalgesic effects through the endocannabinoid system with alkamides, while EP4-R-BU exhibited anti-neuropathic properties mainly through chicoric acid. The extracts have therapeutic potential through the activity of alkamides and the protective properties of polyphenols.
PHYTOTHERAPY RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Gaia Pedriali, Daniela Ramaccini, Esmaa Bouhamida, Alessio Branchini, Giulia Turrin, Elisabetta Tonet, Antonella Scala, Simone Patergnani, Mirko Pinotti, Claudio Trapella, Carlotta Giorgi, Elena Tremoli, Gianluca Campo, Giampaolo Morciano, Paolo Pinton
Summary: The molecular composition and activity modulation of the permeability transition pore (PTP) have been extensively studied due to their importance in ischemia reperfusion injury (IRI). The c subunit of ATP synthase (Csub) has been identified as one of the PTP-forming proteins and a target for cardioprotection. This study aims to identify equivalent residues in the human Csub sequence, validate their role in Oligomycin A-mediated PTP inhibition, and understand their relevance in the binding of 1,3,8-Triazaspiro[4.5]decane derivatives as potential inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Laura Micheli, Valentina Ferrara, Titilayo Akande, Mohamad Khatib, Sule Ola Salawu, Clara Ciampi, Elena Lucarini, Lorenzo Di Cesare Mannelli, Nadia Mulinacci, Carla Ghelardini
Summary: This study tested the efficacy of two plant extracts in a rat model of osteoarthritis. The results showed that Anogeissus leiocarpus extract had significant effects in reducing pain and improving motor skills. Therefore, it may be a potential candidate for the treatment of osteoarthritis.
PHYTOTHERAPY RESEARCH
(2023)
Article
Pharmacology & Pharmacy
Laura Micheli, Lorenzo Di Cesare Mannelli, Elena Mosti, Carla Ghelardini, Anna Rita Bilia, Maria Camilla Bergonzi
Summary: The aim of this study was to test the protective and pain reliever effect of thymoquinone (TQ)-loaded formulations in a rat model of tendinopathy induced by carrageenan intra-tendon injection. The results showed that liposomes containing 2 mg/mL of TQ and covered with hyaluronic acid (HA-LP-TQ2) reduced the development of spontaneous nociception and hypersensitivity, providing a long-lasting effect as a new treatment for tendinopathies.
Article
Biochemistry & Molecular Biology
Valentina Ferrara, Alessandra Toti, Elena Lucarini, Carmen Parisio, Laura Micheli, Clara Ciampi, Francesco Margiotta, Letizia Crocetti, Claudia Vergelli, Maria Paola Giovannoni, Lorenzo Di Cesare Mannelli, Carla Ghelardini
Summary: Rheumatoid arthritis is a chronic autoimmune disorder characterized by joint pain, swelling, and movement impairment caused by inflammation-induced cartilage and bone degradation. Recent research has identified FPRs as a potential target for treatment, and AMC3, a novel agonist, has shown efficacy in vitro and in vivo. This study demonstrates the usefulness of AMC3 and lays the foundation for further research.
Article
Biochemistry & Molecular Biology
Elena Lucarini, Laura Micheli, Alessandra Toti, Clara Ciampi, Francesco Margiotta, Lorenzo Di Cesare Mannelli, Carla Ghelardini
Summary: This study evaluated the anti-hyperalgesic efficacy of ALCAR in a model of persistent visceral pain associated with colitis induced by DNBS injection. The results showed that ALCAR significantly reduced visceral hyperalgesia and partially reduced colon damage in rats, suggesting its potential usefulness as a food supplement for patients suffering from IBDs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Davide Illuminati, Claudio Trapella, Vinicio Zanirato, Remo Guerrini, Valentina Albanese, Chiara Sturaro, Simona Stragapede, Davide Malfacini, Greta Compagnin, Martina Catani, Anna Fantinati
Summary: The replacement of (L)-2,6-dimethyl tyrosine (Dmt) with Phenylalanine (Phe) can have a significant impact on bioactivity, affinity, and selectivity. Recent research has explored the use of a non-natural amino acid, (L)-2-methyl tyrosine (Mmt), to modulate steric effects in opioid peptide chains. This study presents a new synthetic strategy to obtain Mmt using a well-known Pd-catalyzed ortho-C(sp(2))-H activation approach. The introduction of the dibenzylamine moiety on a Tyr aromatic nucleus allows for convenient and traceless mono-ortho-methylation. The substitution of Phe(1) with Mmt in the sequence of Nociceptin/orphanin (N/OFQ) neuropeptide analogues is well tolerated in terms of pharmacological profile and bioactivity.
