The First Universal Opioid Ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): Characterization of the In Vitro Profile and In Vivo Behavioral Effects in Mouse Models of Acute Pain and Cocaine-Induced Reward

Khroyan, Taline V.; Polgar, Willma E.; Cami‐Kobeci, Gerta; Husbands, Stephen M.; Zaveri, Nurulain T.; Toll, Lawrence

doi:10.1124/jpet.110.175620

Cited by 66 publications

(77 citation statements)

References 36 publications

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“…More interestingly, antagonist studies have demonstrated that both MOP and NOP receptors contribute to BU08028-induced antinociception in primates. This is in contrast to rodent studies showing that pretreatment with a NOP receptor antagonist potentiated BU08028-induced antinociception (38). Nonetheless, the functional profile of BU08028 in monkeys provides proof of concept that a single molecule with mixed MOP and NOP agonist activity is more potent than selective ligands and devoid of MOP receptor-mediated side effects (17,25).…”

Section: Discussioncontrasting

confidence: 51%

“…The high logP value of BU08028 could contribute to its unique pharmacokinetic profile (30,38). More interestingly, antagonist studies have demonstrated that both MOP and NOP receptors contribute to BU08028-induced antinociception in primates.…”

Section: Discussionmentioning

confidence: 99%

“…However, in vivo functional profiles of these ligands in primates are completely unknown. Among these recently developed ligands, BU08028 emerged from the orvinol series and displays a similar receptor binding profile to buprenorphine, but with better binding affinity (K i , ∼8 nM) and efficacy (∼48% stimulation of [ 35 S]GTPγS binding) on NOP receptors (37,38). Therefore, BU08028 appears to be an ideal pharmacologic agent with mixed MOP/NOP agonist activity that merits further study.…”

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confidence: 99%

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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.

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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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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

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Czoty

Kiguchi

et al. 2016

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

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“…The present study is the first to demonstrate antihypersensitive effects of intrathecally administered bifunctional NOP/MOP ligands in neuropathic and inflammatory pain. Intrathecal BU08028 and SR16435, both of which bind to NOP and MOP with high affinity (K i 5 2-8 nM) and partial efficacy as measured by guanosine 59-O-(3-[ 35 S]thio)triphosphate functional assay (20-50% stimulation) (Khroyan et al, 2007(Khroyan et al, , 2011a, were more potent than intrathecal SCH221510 or morphine for their antihypersensitive effects (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, we studied bifunctional ligands with high affinity and partial agonist activity at NOP and MOP-BU08028 [2-(N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl)-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3a,4,5, 6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one]-but without agonist activity at d-and k-opioid receptors (Khroyan et al, 2007(Khroyan et al, , 2011a, and we compared them with the selective NOP and MOP agonists as well as buprenorphine. In addition, we compared potential tolerance development to the antiallodynic effects of SR16435 and buprenorphine, which have similar duration of actions, after repeated intrathecal administration.…”

Section: Introductionmentioning

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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Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse

Kiguchi

Ding

2020

J of Neuroscience Research

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Following the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) as an endogenous ligand for the NOP receptor, ample evidence has revealed unique functional profiles of the N/OFQ-NOP receptor system. NOP receptors are expressed in key neural substrates involved in pain and reward modulation. In non-human primates (NHPs), NOP receptor activation effectively exerts antinociception and anti-hypersensitivity at the spinal and supraspinal levels. Moreover, NOP receptor activation inhibits dopaminergic transmission and synergistically enhances mu-opioid peptide (MOP) receptor-mediated analgesia. In this article, we discuss the functional profiles of ligands with dual NOP and MOP receptor agonist activities and highlight their optimal functional efficacy for pain relief and drug abuse treatment. Through coactivation of NOP and MOP receptors, bifunctional NOP/MOP receptor "partial" agonists (e.g., AT-121, BU08028, and BU10038) reveal a wider therapeutic window with fewer side effects. These newly developed ligands potently induce antinociception without MOP receptor agonist-associated side effects such as abuse potential, respiratory depression, itch sensation, and physical dependence. In addition, in both rodent and NHP models, bifunctional NOP/MOP receptor agonists can attenuate reward processing and/or the reinforcing effects of opioids and other abused drugs. While a mixed NOP/opioid receptor "full" agonist cebranopadol is undergoing clinical trials, bifunctional NOP/MOP "partial" agonists exhibit promising therapeutic profiles in translational NHP models for the treatment of pain and opioid abuse. This class of drugs demonstrates the therapeutic advantage of NOP and MOP receptor coactivation, indicating a greater potential for future development.

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The First Universal Opioid Ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): Characterization of the In Vitro Profile and In Vivo Behavioral Effects in Mouse Models of Acute Pain and Cocaine-Induced Reward

Cited by 66 publications

References 36 publications

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

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

Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse

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