Advertisement

NOP-Targeted Peptide Ligands

  • Delia Preti
  • Girolamo Caló
  • Remo GuerriniEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 254)

Abstract

The nociceptin/orphanin FQ (N/OFQ)-N/OFQ peptide (NOP) receptor system is widely distributed at both the peripheral and central level where it modulates important biological functions with increasing therapeutic implications. This chapter wants to provide a comprehensive and updated overview focused on the available structure–activity relationship studies on NOP receptor peptide ligands developed through different rational approaches. Punctual modifications and cyclizations of the N/OFQ sequence have been properly combined furnishing potent NOP selective ligands with different pharmacological activities (full and partial agonists, pure antagonists) and enhanced metabolic stability in vivo. The screening of peptide libraries provided a second family of NOP ligands that have been successfully optimized. Moreover, recent findings suggest the possibility to apply different multimerization strategies for the realization of multi-target NOP/opioid receptor ligands or tetrabranched N/OFQ derivatives with extraordinarily prolonged duration of action in vivo. The diverse approaches led to the identification of important pharmacological tools along with drug candidates currently in clinical development such as Rec 0438 (aka UFP-112) for the treatment of overactive bladder and SER 100 (aka ZP120) for the clinical management of systolic hypertension.

Keywords

Nociceptin/orphanin FQ NOP Peptide ligands SAR studies 

Notes

Author Contributions

DP, GC, and RG wrote the chapter and approved its final version.

Declaration of Interests

DP has nothing to declare. GC and RG are inventors of the patent applications WO2006/087340 and U.S. Serial No. 14/782,578 covering UFP-112 and PWT derivatives of N/OFQ, respectively, and are among the founders of the University of Ferrara spin-off company UFPeptides s.r.l., the assignee of these patents.

References

  1. Ambo A, Hamazaki N, Yamada Y, Nakata E, Sasaki Y (2001) Structure-activity studies on nociceptin analogues: ORL1 receptor binding and biological activity of cyclic disulfide-containing analogues of nociceptin peptides. J Med Chem 44(23):4015–4018.  https://doi.org/10.1021/jm010092i CrossRefPubMedGoogle Scholar
  2. Ambo A, Kohara H, Kawano S, Sasaki Y (2007) Opioid receptor-like 1 (ORL1) receptor binding and the biological properties of Ac-Arg-Tyr-Tyr-Arg-Ile-Arg-NH2 and its analogs. J Pept Sci 13(10):672–678.  https://doi.org/10.1002/psc.900 CrossRefPubMedGoogle Scholar
  3. Arduin M, Spagnolo B, Calo’ G, Guerrini R, Carra’ G, Fischetti C, Trapella C, Marzola E, McDonald J, Lambert DG, Regoli D, Salvadori S (2007) Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with Cα,α-dialkylated amino acids. Bioorg Med Chem 15(13):4434–4443.  https://doi.org/10.1016/j.bmc.2007.04.026 CrossRefPubMedGoogle Scholar
  4. Arsequell G, Rosa M, Mayato C, Dorta RL, Gonzalez-Nunez V, Barreto-Valer K, Marcelo F, Calle LP, Vázquez JT, Rodríguez RE, Jiménez-Barbero J, Valencia G (2011) Synthesis, biological evaluation and structural characterization of novel glycopeptide analogues of nociceptin N/OFQ. Org Biomol Chem 9(17):6133–6142.  https://doi.org/10.1039/c1ob05197k CrossRefPubMedGoogle Scholar
  5. Becker JA, Wallace A, Garzon A, Ingallinella P, Bianchi E, Cortese R, Simonin F, Kieffer BL, Pessi A (1999) Ligands for kappa-opioid and ORL1 receptors identified from a conformationally constrained peptide combinatorial library. J Biol Chem 274(39):27513–27522.  https://doi.org/10.1074/jbc.274.39.27513 CrossRefPubMedGoogle Scholar
  6. Bes B, Meunier JC (2003) Identification of a hexapeptide binding region in the nociceptin (ORL1) receptor by photo-affinity labelling with Ac-Arg-Bpa-Tyr-Arg-Trp-Arg-NH2. Biochem Biophys Res Commun 310(3):992–1001.  https://doi.org/10.1016/j.bbrc.2003.09.113 CrossRefPubMedGoogle Scholar
  7. Bigoni R, Rizzi A, Rizzi D, Becker JA, Kieffer BL, Simonin F, Regoli D, Calo’ G (2000) In vitro pharmacological profile of peptide III-BTD: a novel ligand for nociceptin/orphanin FQ and opioid receptors. Life Sci 68(2):233–239.  https://doi.org/10.1016/S0024-3205(00)00931-0 CrossRefGoogle Scholar
  8. Biondi B, Goldin D, Giannini E, Lattanzi R, Negri L, Melchiorri P, Ciocca L, Rocchi R (2006) Novel nociceptin analogues: synthesis and biological activity. Int J Pept Res Ther 12(2):139–144.  https://doi.org/10.1007/s10989-006-9011-x CrossRefGoogle Scholar
  9. Bird MF, Cerlesi MC, Brown M, Malfacini D, Vezzi V, Molinari P, Micheli L, Di Cesare Mannelli L, Ghelardini C, Guerrini R, Calo’ G, Lambert DG (2016) Characterisation of the novel mixed μ-NOP peptide ligand Dermorphin-N/OFQ (DeNo). PLoS One 11(6):e0156897.  https://doi.org/10.1371/journal.pone.0156897 CrossRefPubMedGoogle Scholar
  10. Bracci L, Falciani C, Lelli B, Lozzi L, Runci Y, Pini A, De Montis MG, Tagliamonte A, Neri P (2003) Synthetic peptides in the form of dendrimers become resistant to protease activity. J Biol Chem 278(47):46590–46595.  https://doi.org/10.1074/jbc.M308615200 CrossRefPubMedGoogle Scholar
  11. Calo’ G, Guerrini R (2013) Medicinal chemistry, pharmacology, and biological actions of peptide ligands selective for the nociceptin/orphanin FQ receptor. In: Research and development of opioid-related ligands. ACS symposium series, vol 1131, pp 275–325.  https://doi.org/10.1021/bk-2013-1131.ch015 Google Scholar
  12. Calo’ G, Lambert DG (2018) Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic. Br J Anaesth 121(5):1105–1114.  https://doi.org/10.1016/j.bja.2018.06.024 CrossRefGoogle Scholar
  13. Calo’ G, Rizzi A, Bogoni G, Neugebauer V, Salvadori S, Guerrini R, Bianchi C, Regoli D (1996) The mouse vas deferens: a pharmacological preparation sensitive to nociceptin. Eur J Pharmacol 311(1):R3–R5.  https://doi.org/10.1016/0014-2999(96)00563-8 CrossRefGoogle Scholar
  14. Calo’ G, Guerrini R, Bigoni R, Rizzi A, Marzola G, Okawa H, Bianchi C, Lambert DG, Salvadori S, Regoli D (2000) Characterization of [Nphe1]nociceptin(1-13)NH2, a new selective nociceptin receptor antagonist. Br J Pharmacol 129(6):1183–1193.  https://doi.org/10.1038/sj.bjp.0703169 CrossRefPubMedGoogle Scholar
  15. Calo’ G, Rizzi A, Rizzi D, Bigoni R, Guerrini R, Marzola G, Marti M, McDonald J, Morari M, Lambert DG, Salvadori S, Regoli D (2002) [Nphe1,Arg14,Lys15]nociceptin-NH2, a novel potent and selective antagonist of the nociceptin/orphanin FQ receptor. Br J Pharmacol 136(2):303–311.  https://doi.org/10.1038/sj.bjp.0704706 CrossRefGoogle Scholar
  16. Calo’ G, Lambert DG, Guerrini R (2013) Nociceptin/orphanin FQ. In: Handbook of biologically active peptides, 2nd edn, pp 1577–1585.  https://doi.org/10.1016/B978-0-12-385095-9.00215-3 CrossRefGoogle Scholar
  17. Calo’ G, Rizzi A, Ruzza C, Ferrari F, Pacifico S, Gavioli EC, Salvadori S, Guerrini R (2018) Peptide welding technology – a simple strategy for generating innovative ligands for G protein coupled receptors. Peptides 99:195–204.  https://doi.org/10.1016/j.peptides.2017.10.004 CrossRefPubMedGoogle Scholar
  18. Camarda V, Fischetti C, Anzellotti N, Molinari P, Ambrosio C, Kostenis E, Regoli D, Trapella C, Guerrini R, Severo S, Calo’ G (2009) Pharmacological profile of NOP receptors coupled with calcium signaling via the chimeric protein Gαqi5. Naunyn Schmiedeberg’s Arch Pharmacol 379(6):599–607.  https://doi.org/10.1007/s00210-009-0396-x CrossRefGoogle Scholar
  19. Carra’ G, Calo’ G, Spagnolo B, Guerrini R, Arduin M, Marzola E, Trapella C, Regoli D, Salvadori S (2005) Tryptophan replacement in the nociceptin/orphanin FQ receptor ligand Ac-RYYRWK-NH2. J Pept Res 66(1):39–47.  https://doi.org/10.1111/j.1399-3011.2005.00272.x CrossRefPubMedGoogle Scholar
  20. Cerlesi MC, Ding H, Bird MF, Kiguchi N, Ferrari F, Malfacini D, Rizzi A, Ruzza C, Lambert DG, Ko MC, Calo’ G, Guerrini R (2017) Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13). Eur J Pharmacol 794:115–126.  https://doi.org/10.1016/j.ejphar.2016.11.026 CrossRefPubMedGoogle Scholar
  21. Charoenchai L, Wang H, Wang JB, Aldrich JV (2008) High affinity conformationally constrained nociceptin/orphanin FQ(1-13) amide analogues. J Med Chem 51(15):4385–4387.  https://doi.org/10.1021/jm800394v CrossRefPubMedGoogle Scholar
  22. Daga PR, Zaveri NT (2012) Homology modeling and molecular dynamics simulations of the active state of the nociceptin receptor reveal new insights into agonist binding and activation. Proteins 80(8):1948–1961.  https://doi.org/10.1002/prot.24077 CrossRefPubMedGoogle Scholar
  23. Ding H, Kiguchi N, Yasuda D, Daga PR, Polgar WE, Lu JJ, Czoty PW, Kishioka S, Zaveri NT, Ko MC (2018) A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med 10(456):eaar3483.  https://doi.org/10.1126/scitranslmed.aar3483 CrossRefGoogle Scholar
  24. Dooley CT, Houghten RA (1996) Orphanin FQ: receptor binding and analog structure activity relationships in rat brain. Life Sci 59(1):PL23–PL29.  https://doi.org/10.1016/0024-3205(96)00261-5 CrossRefPubMedGoogle Scholar
  25. Dooley CT, Spaeth CG, Berzetei-Gurske IP, Craymer K, Adapa ID, Brandt SR, Houghten RA, Toll L (1997) Binding and in vitro activities of peptides with high affinity for the nociceptin/orphanin FQ receptor, ORL1. J Pharmacol Exp Ther 283(2):735–741PubMedGoogle Scholar
  26. Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK (2012) Structure of the δ-opioid receptor bound to naltrindole. Nature 485(7398):400–404.  https://doi.org/10.1038/nature11111 CrossRefPubMedGoogle Scholar
  27. Guerrini R, Calo’ G, Rizzi A, Bianchi C, Lazarus LH, Salvadori S, Temussi PA, Regoli D (1997) Address and message sequences for the nociceptin receptor: a structure-activity study of nociceptin-(1-13)-peptide amide. J Med Chem 40(12):1789–1793.  https://doi.org/10.1021/jm970011b CrossRefPubMedGoogle Scholar
  28. Guerrini R, Calo’ G, Bigoni R, Rizzi D, Rizzi A, Zucchini M, Varani K, Hashiba E, Lambert DG, Toth G, Borea PA, Salvadori S, Regoli D (2001) Structure-activity studies of the Phe4 residue of nociceptin(1-13)-NH2: identification of highly potent agonists of the nociceptin/orphanin FQ receptor. J Med Chem 44(23):3956–3964.  https://doi.org/10.1021/jm010221v CrossRefPubMedGoogle Scholar
  29. Guerrini R, Marzola E, Trapella C, Pela’ M, Molinari S, Cerlesi MC, Malfacini D, Rizzi A, Salvadori S, Calo’ G (2014) A novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ. Bioorg Med Chem 22(14):3703–3712.  https://doi.org/10.1016/j.bmc.2014.05.005 CrossRefPubMedGoogle Scholar
  30. Guerrini R, Marzola E, Trapella C, Pacifico S, Cerlesi MC, Malfacini D, Ferrari F, Bird MF, Lambert DG, Salvadori S, Calo’ G (2015) Structure activity studies of nociceptin/orphanin FQ(1-13)-NH2 derivatives modified in position 5. Bioorg Med Chem 23(7):1515–1520.  https://doi.org/10.1016/j.bmc.2015.02.008 CrossRefPubMedGoogle Scholar
  31. Guillemyn K, Starnowska J, Lagard C, Dyniewicz J, Rojewska E, Mika J, Chung NN, Utard V, Kosson P, Lipkowski AW, Chevillard L, Arranz-Gibert P, Teixidó M, Megarbane B, Tourwé D, Simonin F, Przewlocka B, Schiller PW, Ballet S (2016) Bifunctional peptide-based opioid agonist-nociceptin antagonist ligands for dual treatment of acute and neuropathic pain. J Med Chem 59(8):3777–3792.  https://doi.org/10.1021/acs.jmedchem.5b01976 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Gündüz O, Rizzi A, Baldisserotto A, Guerrini R, Spagnolo B, Gavioli EC, Kocsis L, Magyar A, Benyhe S, Borsodi A, Calo’ G (2006) In vitro and in vivo pharmacological characterization of the nociceptin/orphanin FQ receptor ligand Ac-RYYRIK-ol. Eur J Pharmacol 539(1–2):39–48.  https://doi.org/10.1016/j.ejphar.2006.03.075 CrossRefPubMedGoogle Scholar
  33. Günther T, Dasgupta P, Mann A, Miess E, Kliewer A, Fritzwanker S, Steinborn R, Schulz S (2018) Targeting multiple opioid receptors-improved analgesics with reduced side effects? Br J Pharmacol 175(14):2857–2868.  https://doi.org/10.1111/bph.13809 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Halab L, Becker JA, Darula Z, Tourwe D, Kieffer BL, Simonin F, Lubell WD (2002) Probing opioid receptor interactions with azacycloalkane amino acids. Synthesis of a potent and selective ORL1 antagonist. J Med Chem 45(24):5353–5357.  https://doi.org/10.1021/jm020078l CrossRefPubMedGoogle Scholar
  35. Harrison RS, Ruiz-Gómez G, Hill TA, Chow SY, Shepherd NE, Lohman RJ, Abbenante G, Hoang HN, Fairlie DP (2010) Novel helix-constrained nociceptin derivatives are potent agonists and antagonists of ERK phosphorylation and thermal analgesia in mice. J Med Chem 53(23):8400–8408.  https://doi.org/10.1021/jm101139f CrossRefPubMedGoogle Scholar
  36. Hashiba E, Harrison C, Galo G, Guerrini R, Rowbotham DJ, Smith G, Lambert DG (2001) Characterisation and comparison of novel ligands for the nociceptin/orphanin FQ receptor. Naunyn Schmiedeberg’s Arch Pharmacol 362:28–33.  https://doi.org/10.1007/s002100000327 CrossRefGoogle Scholar
  37. Judd AK, Kaushanskaya A, Tuttle DJ, Sanchez A, Khroyan T, Polgar W, Toll L (2003) N-terminal modifications leading to peptide ORL1 partial agonists and antagonists. J Pept Res 62(5):191–198.  https://doi.org/10.1034/j.1399-3011.2003.00077.x CrossRefPubMedGoogle Scholar
  38. Judd AK, Tuttle DJ, Jones RW, Sanchez A, Polgar W, Berzetei-Gurske I, Toll L (2004) Structure-activity studies on high affinity NOP-active hexapeptides. J Pept Res 64(3):87–94.  https://doi.org/10.1111/j.1399-3011.2004.00169.x CrossRefPubMedGoogle Scholar
  39. Kantola I, Scheinin M, Gulbrandsen T, Meland N, Smerud KT (2017) Safety, tolerability, and antihypertensive effect of SER100, an opiate receptor-like 1 (ORL-1) partial agonist, in patients with isolated systolic hypertension. Clin Pharmacol Drug Dev 6(6):584–591.  https://doi.org/10.1002/cpdd.330 CrossRefPubMedGoogle Scholar
  40. Kapusta DR, Thorkildsen C, Kenigs VA, Meier E, Vinge MM, Quist C, Petersen JS (2005) Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity. J Pharmacol Exp Ther 314(2):652–660.  https://doi.org/10.1124/jpet.105.083436 CrossRefPubMedGoogle Scholar
  41. Kasakov L, Nashar M, Naydenova E, Vezenkov L, Vlaskovska M (2010) In vitro studies of the activity of newly sinthesized nociceptin/orphanin FQ receptor ligand analogues. Protein Pept Lett 17(5):616–620.  https://doi.org/10.2174/092986610791112747 CrossRefPubMedGoogle Scholar
  42. Kawano C, Okada K, Honda T, Nose T, Sakaguchi K, Costa T, Shimohigashi Y (2002) Structural requirements of nociceptin antagonist Ac-RYYRIK-NH2 for receptor binding. J Pept Sci 8(10):561–569.  https://doi.org/10.1002/psc.415 CrossRefPubMedGoogle Scholar
  43. Kawano S, Ambo A, Sasaki Y (2006) Synthesis and receptor binding properties of chimeric peptides containing a mu-opioid receptor ligand and nociceptin/orphanin FQ receptor ligand Ac-RYYRIK-amide. Bioorg Med Chem Lett 16(18):4839–4841.  https://doi.org/10.1016/j.bmcl.2006.06.060 CrossRefPubMedGoogle Scholar
  44. Kawano S, Ito R, Nishiyama M, Kubo M, Matsushima T, Minamisawa M, Ambo A, Sasaki Y (2007) Receptor binding properties and antinociceptive effects of chimeric peptides consisting of a micro-opioid receptor agonist and an ORL1 receptor antagonist. Biol Pharm Bull 30(7):1260–1264.  https://doi.org/10.1248/bpb.30.1260 CrossRefPubMedGoogle Scholar
  45. Kitayama M, Barnes TA, Carra’ G, McDonald J, Calo’ G, Guerrini R, Rowbotham DJ, Smith G, Lambert DG (2003) Pharmacological profile of the cyclic nociceptin/orphanin FQ analogues c[Cys10,14]N/OFQ(1-14)NH2 and c[Nphe1,Cys10,14]N/OFQ(1-14)NH2. Naunyn Schmiedeberg’s Arch Pharmacol 368(6):528–537.  https://doi.org/10.1007/s00210-003-0821-5 CrossRefGoogle Scholar
  46. Kocsis L, Orosz G, Magyar A, Al-Khrasani M, Kató E, Rónai AZ, Bes B, Meunier JC, Gündüz O, Tóth G, Borsodi A, Benyhe S (2004) Nociceptin antagonism: probing the receptor by N-acetyl oligopeptides. Regul Pept 122(3):199–207.  https://doi.org/10.1016/j.regpep.2004.06.019 CrossRefPubMedGoogle Scholar
  47. Lagard C, Chevillard L, Guillemyn K, Risède P, Laplanche JL, Spetea M, Ballet S, Mégarbane B (2017) Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain. Pain 158(3):505–515.  https://doi.org/10.1097/j.pain.0000000000000790 CrossRefPubMedGoogle Scholar
  48. Larsen BD (1999) Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis. WO 99/46283Google Scholar
  49. Li J, Isozaki K, Okada K, Matsushima A, Nose T, Costa T, Shimohigashi Y (2008) Designed modification of partial agonist of ORL1 nociceptin receptor for conversion into highly potent antagonist. Bioorg Med Chem 16(5):2635–2644.  https://doi.org/10.1016/j.bmc.2007.11.043 CrossRefPubMedGoogle Scholar
  50. Lohman RJ, Harrison RS, Ruiz-Gómez G, Hoang HN, Shepherd NE, Chow S, Hill TA, Madala PK, Fairlie DP (2015) Helix-constrained nociceptin peptides are potent agonists and antagonists of ORL-1 and nociceptin. Vitam Horm 97:1–55.  https://doi.org/10.1016/bs.vh.2014.10.001 CrossRefPubMedGoogle Scholar
  51. Malfacini D, Ambrosio C, Gro’ MC, Sbraccia M, Trapella C, Guerrini R, Bonora M, Pinton P, Costa T, Calo’ G (2015) Pharmacological profile of nociceptin/orphanin FQ receptors interacting with G-proteins and beta-arrestins 2. PLoS One 10(8):e0132865.  https://doi.org/10.1371/journal.pone.0132865 CrossRefPubMedGoogle Scholar
  52. Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485(7398):321–326.  https://doi.org/10.1038/nature10954 CrossRefPubMedGoogle Scholar
  53. McDonald J, Barnes TA, Calo’ G, Guerrini R, Rowbotham DJ, Lambert DG (2002) Effects of [(pF)Phe4]nociceptin/orphanin FQ-(1-13)NH2 on GTPγ35S binding and cAMP formation in Chinese hamster ovary cells expressing the human nociceptin/orphanin FQ receptor. Eur J Pharmacol 443(1–3):7–12.  https://doi.org/10.1016/S0014-2999(02)01577-7 CrossRefPubMedGoogle Scholar
  54. McDonald J, Calo’ G, Guerrini R, Lambert DG (2003) UFP-101, a high affinity antagonist for the nociceptin/orphanin FQ receptor: radioligand and GTPγ35S binding studies. Naunyn Schmiedeberg’s Arch Pharmacol 367(2):183–187.  https://doi.org/10.1007/s00210-002-0661-8 CrossRefGoogle Scholar
  55. Molinari S, Camarda V, Rizzi A, Marzola G, Salvadori S, Marzola E, Molinari P, McDonald J, Ko MC, Lambert DG, Calo’ G, Guerrini R (2013) [Dmt1]N/OFQ(1-13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist. Br J Pharmacol 168(1):151–162.  https://doi.org/10.1111/j.1476-5381.2012.02115.x CrossRefPubMedGoogle Scholar
  56. Mustazza C, Pieretti S, Marzoli F (2018) Nociceptin/orphanin FQ peptide (NOP) receptor modulators: an update in structure-activity relationships. Curr Med Chem 25(20):2353–2384.  https://doi.org/10.2174/0929867325666180111095458 CrossRefPubMedGoogle Scholar
  57. Naydenova ED, Todorov PT, Mateeva PI, Zamfirova RN, Pavlov ND, Todorov SB (2010) Synthesis and biological activity of novel small peptides with aminophosphonates moiety as NOP receptor ligands. Amino Acids 39(5):1537–1543.  https://doi.org/10.1007/s00726-010-0624-1 CrossRefPubMedGoogle Scholar
  58. Okada K, Sujaku T, Chuman Y, Nakashima R, Nose T, Costa T, Yamada Y, Yokoyama M, Nagahisa A, Shimohigashi Y (2000) Highly potent nociceptin analog containing the Arg-Lys triple repeat. Biochem Biophys Res Commun 278(2):493–498.  https://doi.org/10.1006/bbrc.2000.3822 CrossRefPubMedGoogle Scholar
  59. Okada K, Isozaki K, Li J, Matsushima A, Nose T, Costa T, Shimohigashi Y (2008) Synergistic effect of basic residues at positions 14-15 of nociceptin on binding affinity and receptor activation. Bioorg Med Chem 16(20):9261–9267.  https://doi.org/10.1016/j.bmc.2008.09.014 CrossRefPubMedGoogle Scholar
  60. Orsini MJ, Nesmelova I, Young HC, Hargittai B, Beavers MP, Liu J, Connolly PJ, Middleton SA, Mayo KH (2005) The nociceptin pharmacophore site for opioid receptor binding derived from the NMR structure and bioactivity relationships. J Biol Chem 280(9):8134–8142.  https://doi.org/10.1074/jbc.M406405200 CrossRefPubMedGoogle Scholar
  61. Pacifico S, Carotenuto A, Brancaccio D, Novellino E, Marzola E, Ferrari F, Cerlesi MC, Trapella C, Preti D, Salvadori S, Calo’ G, Guerrini R (2017) Structure-and conformation-activity studies of nociceptin/orphanin FQ receptor dimeric ligands. Sci Rep 7:45817.  https://doi.org/10.1038/srep45817 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Rizzi D, Rizzi A, Bigoni R, Camarda V, Marzola G, Guerrini R, De Risi C, Regoli D, Calo’ G (2002a) [Arg14,Lys15]nociceptin, a highly potent agonist of the nociceptin/orphanin FQ receptor: in vitro and in vivo studies. J Pharmacol Exp Ther 300(1):57–63.  https://doi.org/10.1124/jpet.300.1.57 CrossRefPubMedGoogle Scholar
  63. Rizzi A, Rizzi D, Marzola G, Regoli D, Larsen BD, Petersen JS, Calo’ G (2002b) Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand, ZP120: in vitro and in vivo studies in mice. Br J Pharmacol 137(3):369–374.  https://doi.org/10.1038/sj.bjp.0704894 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Rizzi A, Malfacini D, Cerlesi MC, Ruzza C, Marzola E, Bird MF, Rowbotham DJ, Salvadori S, Guerrini R, Lambert DG, Calo’ G (2014) In vitro and in vivo pharmacological characterization of nociceptin/orphanin FQ tetrabranched derivatives. Br J Pharmacol 171(17):4138–4153.  https://doi.org/10.1111/bph.12799 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Rizzi A, Sukhtankar DD, Ding H, Hayashida K, Ruzza C, Guerrini R, Calo’ G, Ko MC (2015) Spinal antinociceptive effects of the novel NOP receptor agonist PWT2-nociceptin/orphanin FQ in mice and monkeys. Br J Pharmacol 172(14):3661–3670.  https://doi.org/10.1111/bph.13150 CrossRefPubMedGoogle Scholar
  66. Starnowska J, Guillemyn K, Makuch W, Mika J, Ballet S, Przewlocka B (2017) Bifunctional opioid/nociceptin hybrid KGNOP1 effectively attenuates pain-related behaviour in a rat model of neuropathy. Eur J Pharm Sci 104:221–229.  https://doi.org/10.1016/j.ejps.2017.03.029 CrossRefPubMedGoogle Scholar
  67. Tancredi T, Carra’ G, Guerrini R, Arduin M, Calo’ G, Regoli D, Salvadori S, Temussi PA (2005) The interaction of highly helical structural mutants with the NOP receptor discloses the role of the address domain of nociceptin/orphanin FQ. Chemistry 11(7):2061–2070.  https://doi.org/10.1002/chem.200401095 CrossRefPubMedGoogle Scholar
  68. Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo’ G, Roth BL, Cherezov V, Stevens RC (2012) Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485(7398):395–399.  https://doi.org/10.1038/nature11085 CrossRefPubMedGoogle Scholar
  69. Todorov PT, Mateeva PI, Zamfirova RN, Pavlov ND, Naydenova ED (2012) Synthesis and biological activity of new series of N-modified analogues of the N/OFQ(1-13)NH2 with aminophosphonate moiety. Amino Acids 43(3):1217–1223.  https://doi.org/10.1007/s00726-011-1177-7 CrossRefPubMedGoogle Scholar
  70. Toll L, Bruchas MR, Calo’ G, Cox BM, Zaveri NT (2016) Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68(2):419–457.  https://doi.org/10.1124/pr.114.009209 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Van Cauwenberghe S, Simonin F, Cluzeau J, Becker JA, Lubell WD, Tourwe D (2004) Structure-activity study of the ORL1 antagonist Ac-Arg-D-Cha-Qaa-D-Arg-D-p-ClPhe-NH2. J Med Chem 47(7):1864–1867.  https://doi.org/10.1021/jm031034v CrossRefPubMedGoogle Scholar
  72. Wright KE, McDonald J, Barnes TA, Rowbotham DJ, Guerrini R, Calo’ G, Lambert DG (2003) Assessment of the activity of a novel nociceptin/orphanin FQ analogue at recombinant human nociceptin/orphanin FQ receptors expressed in Chinese hamster ovary cells. Neurosci Lett 346(3):145–148.  https://doi.org/10.1016/S0304-3940(03)00518-4 CrossRefPubMedGoogle Scholar
  73. Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012) Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485(7398):327–332.  https://doi.org/10.1038/nature10939 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Zamfirova R, Pavlov N, Todorov P, Mateeva P, Martinez J, Calmes M, Naydenova E (2013) Synthesis and changes in affinity for NOP and opioid receptors of novel hexapeptides containing β2-tryptophan analogues. Bioorg Med Chem Lett 23(14):4052–4055.  https://doi.org/10.1016/j.bmcl.2013.05.064 CrossRefPubMedGoogle Scholar
  75. Zaveri NT (2016) Nociceptin Opioid Receptor (NOP) as a therapeutic target: progress in translation from preclinical research to clinical utility. J Med Chem 59(15):7011–7028.  https://doi.org/10.1021/acs.jmedchem.5b01499 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Zhang C, Miller W, Valenzano KJ, Kyle DJ (2012) Novel, potent ORL-1 receptor agonist peptides containing alpha-Helix-promoting conformational constraints. J Med Chem 45(24):5280–5286.  https://doi.org/10.1021/jm0202021 CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Chemical and Pharmaceutical SciencesUniversity of FerraraFerraraItaly
  2. 2.Department of Medical Sciences, Section of PharmacologyUniversity of Ferrara and National Institute of NeurosciencesFerraraItaly

Personalised recommendations