A novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ

Guerrini, Remo; Marzola, Erika; Trapella, Claudio; Pelà, Michela; Molinari, Stefano; Cerlesi, Maria Camilla; Malfacini, Davide; Rizzi, Anna; Salvadori, Severo; Calò, Girolamo

doi:10.1016/j.bmc.2014.05.005

Cited by 31 publications

(54 citation statements)

References 42 publications

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“…In the electrically stimulated mouse vas deferens, these compounds mimicked the inhibitory action of the natural sequence with similar maximal effects and threefold higher potencies. The NOPselective antagonist SB-612111 antagonized the effects of N/OFQ and PWT derivatives with similar pKB values (8.02-8.48) (Guerrini et al, 2014). In vivo after supraspinal administration, PWT2-N/OFQ stimulated food intake in mice (Guerrini et al, 2014) and mimicked the inhibitory effects exerted by N/OFQ on locomotor activity .…”

Section: Introductionmentioning

confidence: 88%

“…In vitro these compounds maintained the biological activity, potency and selectivity of action of the natural peptide. In vivo PWT derivatives showed higher potency and a marked prolongation of action compared with the natural sequences (Guerrini et al, 2014;Rizzi et al, 2014;Ruzza et al, 2014;.…”

Section: Introductionmentioning

confidence: 95%

“…Peptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multi-branched peptides with extraordinarily high yield, purity and reproducibility (Guerrini et al, 2014). Using this approach, different tetrabranched derivatives of endogenous peptides, including nociceptin/orphanin FQ (N/OFQ), substance P, neurokinins A and B, and more recently neuropeptide S, have been synthesized and characterized.…”

Section: Introductionmentioning

confidence: 99%

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Spinal antinociceptive effects of the novel NOP receptor agonist PWT2‐nociceptin/orphanin FQ in mice and monkeys

Rizzi

Sukhtankar

Ding

et al. 2015

British J Pharmacology

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Background and purposeUsing an innovative chemical approach, peptide welding technology (PWT), a tetrabranched derivative of nociceptin/orphanin FQ (N/OFQ) has been generated and pharmacologically characterized. Both in vitro and in vivo PWT2‐N/OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer‐lasting effects. The aim of the present study was to investigate the spinal effects of PWT2‐N/OFQ in nociceptive and neuropathic pain models in mice and non‐human primates.Experimental ApproachTail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N/OFQ and PWT2‐N/OFQ were assessed in these models.Key ResultsPWT2‐N/OFQ mimicked the spinal antinociceptive effects of N/OFQ both in nociceptive and neuropathic pain models in mice as well as in non‐human primates displaying 40‐fold higher potency and a markedly prolonged duration of action. The effects of N/OFQ and PWT2‐N/OFQ were sensitive to the N/OFQ receptor (NOP) antagonist SB‐612111, but not to opioid receptor antagonists.Conclusions and ImplicationsThe present study has demonstrated that PWT2‐N/OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non‐human primates acting as a potent and longer‐lasting NOP‐selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Spinal antinociceptive effects of the novel NOP receptor agonist PWT2‐nociceptin/orphanin FQ in mice and monkeys

Rizzi

Sukhtankar

Ding

et al. 2015

British J Pharmacology

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“…Recently a novel and facile chemical strategy for the synthesis of tetrabranched peptides named peptide welding technology (PWT; Guerrini et al, 2014) was used to prepare three N/OFQ tetrabranched derivatives containing different cores (PWT1, PWT2, and PWT3). PWT derivatives of N/OFQ behaved as high affinity, potent full agonists with respect to receptor binding, […”

Section: A Nociceptin/orphanin Fq Related Peptidesmentioning

confidence: 99%

“…Interestingly, when measuring calcium mobilization in cells expressing chimeric G-proteins , the potency of ZP120 was relatively low, as was the case with several other NOP ligands such as UFP-112, UFP-113, and PWT2-N/OFQ (see Table 2). Each of these compounds is characterized by a slow kinetics of activation of the NOP receptor, as suggested by bioassay experiments in isolated tissues (Rizzi et al, 2002c;Calo' et al, 2011;Guerrini et al, 2014). It is possible that the rapid kinetics that characterize the calcium transient response may be incompatible with the slow kinetics of the ligand receptor interaction (for a detailed discussion of this topic see Camarda et al, 2009;Rizzi et al, 2014).…”

Section: B Nociceptin/orphanin Fq Unrelated Peptidesmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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In vitro and in vivo pharmacological characterization of a neuropeptide S tetrabranched derivative

Ruzza

Rizzi

Malfacini

et al. 2015

Pharmacology Res & Perspec

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The peptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity, and reproducibility. With this approach, a tetrabranched derivative of neuropeptide S (NPS) has been synthesized and pharmacologically characterized. The in vitro activity of PWT1-NPS has been studied in a calcium mobilization assay. In vivo, PWT1-NPS has been investigated in the locomotor activity (LA) and recovery of the righting reflex (RR) tests. In calcium mobilization studies, PWT1-NPS behaved as full agonist at the mouse NPS receptor (NPSR) being threefold more potent than NPS. The selective NPSR antagonists [tBu-D-Gly5]NPS and SHA 68 displayed similar potency values against NPS and PWT1-NPS. In vivo, both NPS (1–100 pmol, i.c.v.) and PWT1-NPS (0.1–100 pmol, i.c.v.) stimulated mouse LA, with PWT1-NPS showing higher potency than NPS. In the RR assay, NPS (100 pmol, i.c.v.) was able to reduce the percentage of mice losing the RR after diazepam administration and their sleep time 5 min after the i.c.v. injection, but it was totally inactive 2 h after the injection. On the contrary, PWT1-NPS (30 pmol, i.c.v.), injected 2 h before diazepam, displayed wake-promoting effects. This PWT1-NPS stimulant effect was no longer evident in mice lacking the NPSR receptor. The PWT1 technology can be successfully applied to the NPS sequence. PWT1-NPS displayed in vitro a pharmacological profile similar to NPS. In vivo PWT1-NPS mimicked NPS effects showing higher potency and long-lasting action.

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A novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ

Cited by 31 publications

References 42 publications

Spinal antinociceptive effects of the novel NOP receptor agonist PWT2‐nociceptin/orphanin FQ in mice and monkeys

Spinal antinociceptive effects of the novel NOP receptor agonist PWT2‐nociceptin/orphanin FQ in mice and monkeys

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

In vitro and in vivo pharmacological characterization of a neuropeptide S tetrabranched derivative

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