ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Triazine Compounds as Antagonists at Bv8-Prokineticin Receptors

View Author Information
Department of Pharmaceutical Sciences, University of Ferrara, I-44100 Ferrara, Italy, Department of Physiology and Pharmacology “Vittorio Erspamer”, University “La Sapienza”, I-00185 Rome, Italy, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy, Department of Toxicology, University of Cagliari, I-09124, Cagliari, Italy
* To whom correspondence should be addressed. Phone: (+39)-70-675-8625. Fax: (+39)-70-675-8612. E-mail: [email protected]; [email protected]
†Department of Pharmaceutical Sciences, University of Ferrara.
∥Department of Toxicology, University of Cagliari.
‡Department of Physiology and Pharmacology “Vittorio Erspamer”, University “La Sapienza”.
§Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità.
Cite this: J. Med. Chem. 2008, 51, 23, 7635–7639
Publication Date (Web):November 12, 2008
Copyright © 2008 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    On the basis of a Janssen’s patent, we approached a new synthesis of some 1,3,5-triazin-4,6-diones as potential non peptidic prokineticin receptor antagonists, containing the following substitutions: (N1 and N5 link a 4-methoxybenzyl and a 4-ethylbenzyl, respectively; C2 can link an amino-ethyl-guanidine (reference compound 1) or an ethylendiamine (2) or an amino-ethyl-amino-2-imidazoline (3). New compounds were assessed for PKR1 and PKR2 affinity. Antagonist properties were evaluated as inhibition of 1 nM Bv8-induced intracellular Ca2+ mobilization.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    Chemistry general methods, patented synthetic scheme of Reference 1, receptor binding assay, figures 1 and 2 related to prokineticin receptors binding, elemental analysis and MS data. This material is available free of charge via the Internet at

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 52 publications.

    1. Jaoon Y. H. Kim, Jae Wook Lee, Woo Sirl Lee, Hyung-Ho Ha, Marc Vendrell, Jacqueline T. Bork, Youngsook Lee, and Young-Tae Chang . Combinatorial Solid-Phase Synthesis of 4,6-Diaryl and 4-Aryl, 6-Alkyl-1,3,5-triazines and Their Application to Efficient Biofuel Production. ACS Combinatorial Science 2012, 14 (7) , 395-398.
    2. Gloria Ruiz-Gómez, Joel D. A. Tyndall, Bernhard Pfeiffer, Giovanni Abbenante, and David P. Fairlie. Update 1 of: Over One Hundred Peptide-Activated G Protein-Coupled Receptors Recognize Ligands with Turn Structure. Chemical Reviews 2010, 110 (4) , PR1-PR41.
    3. Martina Vincenzi, Amin Kremić, Appoline Jouve, Roberta Lattanzi, Rossella Miele, Mohamed Benharouga, Nadia Alfaidy, Stephanie Migrenne-Li, Anumantha G. Kanthasamy, Marimelia Porcionatto, Napoleone Ferrara, Igor V. Tetko, Laurent Désaubry, Canan G. Nebigil, . Therapeutic Potential of Targeting Prokineticin Receptors in Diseases. Pharmacological Reviews 2023, 75 (6) , 1167-1199.
    4. Hadi Younes, Ioanna Kyritsi, Zineb Mahrougui, Mohamed Benharouga, Nadia Alfaidy, Christel Marquette. Effects of Prokineticins on Cerebral Cell Function and Blood–Brain Barrier Permeability. International Journal of Molecular Sciences 2023, 24 (20) , 15428.
    5. Giulia Galimberti, Giada Amodeo, Giulia Magni, Benedetta Riboldi, Gianfranco Balboni, Valentina Onnis, Stefania Ceruti, Paola Sacerdote, Silvia Franchi. Prokineticin System Is a Pharmacological Target to Counteract Pain and Its Comorbid Mood Alterations in an Osteoarthritis Murine Model. Cells 2023, 12 (18) , 2255.
    6. Daniela Impellizzeri, Daniela Maftei, Cinzia Severini, Rossella Miele, Gianfranco Balboni, Rosalba Siracusa, Marika Cordaro, Rosanna Di Paola, Salvatore Cuzzocrea, Roberta Lattanzi. Blocking prokineticin receptors attenuates synovitis and joint destruction in collagen-induced arthritis. Journal of Molecular Medicine 2023, 101 (5) , 569-580.
    7. Roberta Lattanzi, Rossella Miele. Non-Peptide Agonists and Antagonists of the Prokineticin Receptors. Current Issues in Molecular Biology 2022, 44 (12) , 6323-6332.
    8. Roberta Lattanzi, Rossella Miele. Prokineticin-Receptor Network: Mechanisms of Regulation. Life 2022, 12 (2) , 172.
    9. Laura Rullo, Silvia Franchi, Giada Amodeo, Francesca Felicia Caputi, Benedetta Verduci, Loredana Maria Losapio, Paola Sacerdote, Patrizia Romualdi, Sanzio Candeletti. Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy. International Journal of Molecular Sciences 2021, 22 (21) , 11913.
    10. Roberta Lattanzi, Cinzia Severini, Daniela Maftei, Luciano Saso, Aldo Badiani. The Role of Prokineticin 2 in Oxidative Stress and in Neuropathological Processes. Frontiers in Pharmacology 2021, 12
    11. Deborah Reynaud, Frederic Sergent, Roland Abi Nahed, Wael Traboulsi, Constance Collet, Christel Marquette, Pascale Hoffmann, Gianfranco Balboni, Qun-Yong Zhou, Padma Murthi, Mohamed Benharouga, Nadia Alfaidy. Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy. Biomedicines 2021, 9 (3) , 309.
    12. Jongsoo Mok, Tae Sub Park, Sunhong Kim, Daehoon Kim, Cheol Soo Choi, Joonghoon Park. Prokineticin receptor 1 ameliorates insulin resistance in skeletal muscle. The FASEB Journal 2021, 35 (2)
    13. Giorgia Moschetti, Theodora Kalpachidou, Giada Amodeo, Roberta Lattanzi, Paola Sacerdote, Michaela Kress, Silvia Franchi. Prokineticin Receptor Inhibition With PC1 Protects Mouse Primary Sensory Neurons From Neurotoxic Effects of Chemotherapeutic Drugs in vitro. Frontiers in Immunology 2020, 11
    14. Cosmin I. Ciotu, Michael J.M. Fischer. Novel Analgesics with Peripheral Targets. Neurotherapeutics 2020, 17 (3) , 784-825.
    15. Giorgia Moschetti, Giada Amodeo, Daniela Maftei, Roberta Lattanzi, Patrizia Procacci, Patrizia Sartori, Gianfranco Balboni, Valentina Onnis, Vincenzo Conte, Alberto Panerai, Paola Sacerdote, Silvia Franchi. Targeting prokineticin system counteracts hypersensitivity, neuroinflammation, and tissue damage in a mouse model of bortezomib-induced peripheral neuropathy. Journal of Neuroinflammation 2019, 16 (1)
    16. Giorgia Moschetti, Giada Amodeo, Maria Serena Paladini, Raffaella Molteni, Gianfranco Balboni, Alberto Panerai, Paola Sacerdote, Silvia Franchi. Prokineticin 2 promotes and sustains neuroinflammation in vincristine treated mice: Focus on pain and emotional like behavior. Brain, Behavior, and Immunity 2019, 82 , 422-431.
    17. Daniela Maftei, Patrizia Ratano, Ilaria Fusco, Veronica Marconi, Silvia Squillace, Lucia Negri, Cinzia Severini, Gianfranco Balboni, Luca Steardo, Maria Rosanna Bronzuoli, Caterina Scuderi, Patrizia Campolongo, Roberta Lattanzi. The prokineticin receptor antagonist PC1 rescues memory impairment induced by β amyloid administration through the modulation of prokineticin system. Neuropharmacology 2019, 158 , 107739.
    18. Anna Rita Zuena, Paola Casolini, Roberta Lattanzi, Daniela Maftei. Chemokines in Alzheimer’s Disease: New Insights Into Prokineticins, Chemokine-Like Proteins. Frontiers in Pharmacology 2019, 10
    19. Roberta Lattanzi, Daniela Maftei, Maria Rosaria Fullone, Rossella Miele. Identification and characterization of Prokineticin receptor 2 splicing variant and its modulation in an animal model of Alzheimer's disease. Neuropeptides 2019, 73 , 49-56.
    20. Roberta Lattanzi, Daniela Maftei, Lucia Negri, Ilaria Fusco, Rossella Miele. PK2β ligand, a splice variant of prokineticin 2, is able to modulate and drive signaling through PKR1 receptor. Neuropeptides 2018, 71 , 32-42.
    21. Lucia Negri, Napoleone Ferrara. The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis. Physiological Reviews 2018, 98 (2) , 1055-1082.
    22. Silvia Caioli, Cinzia Severini, Teresa Ciotti, Fulvio Florenzano, Domenico Pimpinella, Pamela Petrocchi Passeri, Gianfranco Balboni, Patrizio Polisca, Roberta Lattanzi, Robert Nisticò, Lucia Negri, Cristina Zona. Prokineticin system modulation as a new target to counteract the amyloid beta toxicity induced by glutamatergic alterations in an in vitro model of Alzheimer's disease. Neuropharmacology 2017, 116 , 82-97.
    23. Canan G. Nebigil. Updates on Endothelial Functions of Proangiogenic Prokineticin. Hypertension 2016, 68 (5) , 1091-1097.
    24. Jeanette Prinz, Ingo Vogt, Gianluca Adornetto, Mónica Campillos, . A Novel Drug-Mouse Phenotypic Similarity Method Detects Molecular Determinants of Drug Effects. PLOS Computational Biology 2016, 12 (9) , e1005111.
    25. Frédéric Sergent, Pascale Hoffmann, Sophie Brouillet, Vanessa Garnier, Aude Salomon, Padma Murthi, Mohamed Benharouga, Jean-Jacques Feige, Nadia Alfaidy. Sustained Endocrine Gland–Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension. Hypertension 2016, 68 (1) , 148-156.
    26. Mara Castelli, Giada Amodeo, Lucia Negri, Roberta Lattanzi, Daniela Maftei, Cecilia Gotti, Francesco Pistillo, Valentina Onnis, Cenzo Congu, Alberto E. Panerai, Paola Sacerdote, Silvia Franchi, . Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes. PLOS ONE 2016, 11 (1) , e0146259.
    27. Cinzia Severini, Roberta Lattanzi, Daniela Maftei, Veronica Marconi, Maria Teresa Ciotti, Pamela Petrocchi Passeri, Fulvio Florenzano, Ester Del Duca, Silvia Caioli, Cristina Zona, Gianfranco Balboni, Severo Salvadori, Robert Nisticò, Lucia Negri. Bv8/prokineticin 2 is involved in Aβ-induced neurotoxicity. Scientific Reports 2015, 5 (1)
    28. Luciano De Petrocellis, Aniello Schiano Moriello, Joon Seok Byun, Joo Mi Sohn, Jae Yeol Lee, Ana Vázquez-Romero, Maria Garrido, Angel Messeguer, Fang-Xiong Zhang, Gerald W. Zamponi, Alessandro Deplano, Cenzo Congiu, Valentina Onnis, Gianfranco Balboni, Vincenzo Di Marzo. Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel. Pharmacological Research 2015, 99 , 362-369.
    29. Mhamad Abou-Hamdan, Massimo Costanza, Elena Fontana, Marco Di Dario, Silvia Musio, Cenzo Congiu, Valentina Onnis, Roberta Lattanzi, Marta Radaelli, Vittorio Martinelli, Severo Salvadori, Lucia Negri, Pietro Luigi Poliani, Cinthia Farina, Gianfranco Balboni, Lawrence Steinman, Rosetta Pedotti. Critical role for prokineticin 2 in CNS autoimmunity. Neurology Neuroimmunology & Neuroinflammation 2015, 2 (3)
    30. Hermann AM Mucke. Patent Highlights. Pharmaceutical Patent Analyst 2015, 4 (3) , 141-146.
    31. Norikazu Sakakibara, Gianfranco Balboni, Cenzo Congiu, Valentina Onnis, Yosuke Demizu, Takashi Misawa, Masaaki Kurihara, Yoshihisa Kato, Tokumi Maruyama, Masaaki Toyama, Mika Okamoto, Masanori Baba. Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives. Antiviral Chemistry and Chemotherapy 2015, 24 (2) , 62-71.
    32. F. Guida, R. Lattanzi, S. Boccella, D. Maftei, R. Romano, V. Marconi, G. Balboni, S. Salvadori, M.A. Scafuro, V. de Novellis, L. Negri, S. Maione, L. Luongo. PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice. Pharmacological Research 2015, 91 , 36-46.
    33. Padma Murthi, Sophie Brouillet, Anita Pratt, Anthony Borg, Bill Kalionis, Frederic Goffin, Vassilis Tsatsaris, Carine Munaut, Jean-Jacques Feige, Mohamed Benharouga, Thierry Fournier, Nadia Alfaidy. An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction. Molecular Medicine 2015, 21 (1) , 645-656.
    34. D Maftei, V Marconi, F Florenzano, L A Giancotti, M Castelli, S Moretti, E Borsani, L F Rodella, G Balboni, L Luongo, S Maione, P Sacerdote, L Negri, R Lattanzi. Controlling the activation of the B v8/prokineticin system reduces neuroinflammation and abolishes thermal and tactile hyperalgesia in neuropathic animals. British Journal of Pharmacology 2014, 171 (21) , 4850-4865.
    35. Muniyappa Krishnamurthy, Basavaprabhu, K.M. Sharanabai, Vommina V. Sureshbabu. A facile route for the synthesis of novel S-linked 1,3,5-triazine tethered peptidomimetics. Tetrahedron Letters 2014, 55 (41) , 5609-5612.
    36. Cenzo Congiu, Valentina Onnis, Alessandro Deplano, Severo Salvadori, Veronica Marconi, Daniela Maftei, Lucia Negri, Roberta Lattanzi, Gianfranco Balboni. A new convenient synthetic method and preliminary pharmacological characterization of triazinediones as prokineticin receptor antagonists. European Journal of Medicinal Chemistry 2014, 81 , 334-340.
    37. Kavita Kumari Kakarala, Kaiser Jamil. Sequence-structure based phylogeny of GPCR Class A Rhodopsin receptors. Molecular Phylogenetics and Evolution 2014, 74 , 66-96.
    38. KEL Beale, JV Gardiner, GA Bewick, K Hostomska, NA Patel, SS Hussain, CN Jayasena, FJP Ebling, PH Jethwa, HM Prosser, R Lattanzi, L Negri, MA Ghatei, SR Bloom, WS Dhillo. Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem. British Journal of Pharmacology 2013, 168 (2) , 403-410.
    39. R Lattanzi, P Sacerdote, S Franchi, M Canestrelli, R Miele, D Barra, S Visentin, C DeNuccio, F Porreca, M De Felice, F Guida, L Luongo, V de Novellis, S Maione, L Negri. Pharmacological activity of a Bv8 analogue modified in position 24. British Journal of Pharmacology 2012, 166 (3) , 950-963.
    40. Michelle Y. Cheng, Alex G. Lee, Collin Culbertson, Guohua Sun, Rushi K. Talati, Nathan C. Manley, Xiaohan Li, Heng Zhao, David M. Lyons, Qun-Yong Zhou, Gary K. Steinberg, Robert M. Sapolsky. Prokineticin 2 is an endangering mediator of cerebral ischemic injury. Proceedings of the National Academy of Sciences 2012, 109 (14) , 5475-5480.
    41. Lucia Negri, Roberta Lattanzi. Bv8/PK2 and prokineticin receptors: a druggable pronociceptive system. Current Opinion in Pharmacology 2012, 12 (1) , 62-66.
    42. Kah Hoe Kong, Chong Kiat Tan, Xijie Lin, Yulin Lam. A Versatile Thiouronium‐Based Solid‐Phase Synthesis of 1,3,5‐Triazines. Chemistry – A European Journal 2012, 18 (5) , 1476-1486.
    43. Anat Levit, Talia Yarnitzky, Ayana Wiener, Rina Meidan, Masha Y. Niv, . Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs. PLoS ONE 2011, 6 (11) , e27990.
    44. Xiaofang Li, Zhikui Li, Aiting Zheng, Guobin Li, Xianyong Yu, Pinggui Yi. Synthesis of dispiro[oxindole‐pyrrolidine]‐thiazolo[3,2‐ a ][1,3,5]triazines by 1,3‐dipolar cycloaddition. Journal of Heterocyclic Chemistry 2011, 48 (4) , 836-839.
    45. Orit Jacobson, Ido D. Weiss, Gang Niu, Gianfranco Balboni, Cenzo Congiu, Valentina Onnis, Dale O. Kiesewetter, Roberta Lattanzi, Severo Salvadori, Xiaoyuan Chen. Prokineticin Receptor 1 Antagonist PC-10 as a Biomarker for Imaging Inflammatory Pain. Journal of Nuclear Medicine 2011, 52 (4) , 600-607.
    46. Shenliang Wang, Woo Sirl Lee, Hyung-Ho Ha, Young-Tae Chang. Combinatorial synthesis of galactosyl-1,3,5-triazines as novel nucleoside analogues. Organic & Biomolecular Chemistry 2011, 9 (20) , 6924.
    47. Xiaofang Li, Haochong Liu, Aiting Zheng, Zhikui Li, Guobin Li, Xianyong Yu, Pinggui Yi. Synthesis of Novel Spiro Thiazolo[3,2‐ a ][1,3,5]triazines via 1,3‐Dipolar Cycloaddition of Azomethine Ylide. Chinese Journal of Chemistry 2011, 29 (1) , 97-101.
    48. Rossella Miele, Roberta Lattanzi, Maria Carmela Bonaccorsi di Patti, Alessandro Paiardini, Lucia Negri, Donatella Barra. Expression of Bv8 in Pichia pastoris to identify structural features for receptor binding. Protein Expression and Purification 2010, 73 (1) , 10-14.
    49. Lev Osherovich. Bv8: main pain player. Science-Business eXchange 2009, 2 (34) , 1299-1299.
    50. Elisa Giannini, Roberta Lattanzi, Annalisa Nicotra, Antonio F. Campese, Paola Grazioli, Isabella Screpanti, Gianfranco Balboni, Severo Salvadori, Paola Sacerdote, Lucia Negri. The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain. Proceedings of the National Academy of Sciences 2009, 106 (34) , 14646-14651.
    51. Janet L. Ralbovsky, Joseph G. Lisko, Jeffrey M. Palmer, John Mabus, Kristen M. Chevalier, Mark J. Schulz, Alexey B. Dyatkin, Tamara A. Miskowski, Steven J. Coats, Pamela Hornby, Wei He. Triazinediones as prokineticin 1 receptor antagonists. Part 1: SAR, synthesis and biological evaluation. Bioorganic & Medicinal Chemistry Letters 2009, 19 (10) , 2661-2663.
    52. Canan G. Nebigil. Prokineticin Receptors in Cardiovascular Function: Foe or Friend?. Trends in Cardiovascular Medicine 2009, 19 (2) , 55-60.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect