<scp>[Dmt<sup>1</sup>]N/OFQ(1–13)‐NH<sub>2</sub></scp>: a potent nociceptin/orphanin <scp>FQ</scp> and opioid receptor universal agonist

Molinari, Stefano; Camarda,; Rizzi, Anna; Marzola, Giuliano; Salvadori, Severo; Marzola, Erika; Molinari, Paola; McDonald, John; Ko, Mei‐Chuan; Lambert, David G.; Calò, Girolamo; Guerrini, Remo

doi:10.1111/j.1476-5381.2012.02115.x

Cited by 40 publications

(45 citation statements)

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“…The antinociceptive properties of NOP agonists given i.t. have been confirmed in non-human primate studies using N/OFQ (Ko et al, 2006;Ko and Naughton, 2009) as well as NOP-selective (Hu et al, 2010) or non-selective (Molinari et al, 2013) compounds. Interestingly, spinal NOP-mediated antinociception is not associated with typical μ-opioid (MOP) receptor side effects such as itch (Lin and Ko, 2013).…”

Section: Introductionmentioning

confidence: 69%

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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: 69%

“…*P < 0.05, significantly different from vehicle controls. 6 h) or with experimentally developed compounds (∼4-6 h) (Ko et al, 2006;Hu et al, 2010;Molinari et al, 2013) .…”

Section: Figurementioning

confidence: 99%

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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“…Subsequent to chemical modifications, some of these ligands exhibited antinociceptive and antihypersensitive efficacy with improved potency across different rodent pain models (31,(34)(35)(36). However, in vivo functional profiles of these ligands in primates are completely unknown.…”

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confidence: 99%

“…Several medicinal chemistry groups have discovered such agonists with varying affinity and efficacy at MOP and NOP receptors (30)(31)(32)(33). Subsequent to chemical modifications, some of these ligands exhibited antinociceptive and antihypersensitive efficacy with improved potency across different rodent pain models (31,(34)(35)(36).…”

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confidence: 99%

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

Ding

Czoty

Kiguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various wellhoned behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10-to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abusefree opioid analgesics.N/OFQ peptide receptor | respiratory depression | reinforcing effects | physical dependence | mu opioid peptide receptor P ain, a symptom of numerous clinical disorders, afflicts millions of people worldwide. Despite the remarkable advances in the identification of potential targets as analgesics in the last decade, mu opioid peptide (MOP) receptor agonists remain the most widely used analgesics for pain management (1). Several side effects associated with MOP receptor agonists have severely limited the value of opioid analgesics, however (2). Owing to the abuse liability and the high mortality rate caused by respiratory arrest, opioid abuse not only has dire consequences, but also leads to mounting medical and economic burdens in our society (3-5). There is a clear, unmet need for safe analgesics without abuse liability in the global community.Buprenorphine, a partial MOP receptor agonist, is considered a safe analgesic because of its ceiling effect on respiratory depression (6, 7). Buprenorphine is commonly used in both human and veterinary medicine to treat various pain conditions, including cancer pain and neuropathic pain (7,8). However, buprenorphine is not devoid of reinforcing effects, the most devastating side effect...

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“…Importantly, our data also indicate that such compounds may have a slower tolerance development to their analgesic effects. These findings further highlight the importance of investigating bifunctional NOP/MOP ligands as a novel therapeutic strategy (Spagnolo et al, 2008;Toll et al, 2009;Cremeans et al, 2012;Molinari et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Effects of Spinally Administered Bifunctional Nociceptin/Orphanin FQ Peptide Receptor/μ-Opioid Receptor Ligands in Mouse Models of Neuropathic and Inflammatory Pain

Sukhtankar¹,

Zaveri²,

Husbands³

et al. 2013

J Pharmacol Exp Ther

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and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphineinduced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/ MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics.

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[Dmt¹]N/OFQ(1–13)‐NH₂: a potent nociceptin/orphanin FQ and opioid receptor universal agonist

Cited by 40 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

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

Effects of Spinally Administered Bifunctional Nociceptin/Orphanin FQ Peptide Receptor/μ-Opioid Receptor Ligands in Mouse Models of Neuropathic and Inflammatory Pain

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[Dmt1]N/OFQ(1–13)‐NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist

Cited by 40 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

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

Effects of Spinally Administered Bifunctional Nociceptin/Orphanin FQ Peptide Receptor/μ-Opioid Receptor Ligands in Mouse Models of Neuropathic and Inflammatory Pain

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[Dmt¹]N/OFQ(1–13)‐NH₂: a potent nociceptin/orphanin FQ and opioid receptor universal agonist