Roles of μ-Opioid Receptors and Nociceptin/Orphanin FQ Peptide Receptors in Buprenorphine-Induced Physiological Responses in Primates

Cremeans, Colette M; Gruley, Erin; Kyle, Donald J.; Ko, Mei‐Chuan

doi:10.1124/jpet.112.194308

Cited by 92 publications

(105 citation statements)

References 38 publications

(76 reference statements)

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“…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: 50%

“…Following spinal and systemic administration, NOP receptor agonists produce antinociception and antihypersensitivity comparable to those of MOP receptor agonists, but without reinforcing effects in nonhuman primates (21)(22)(23)(24). More importantly, NOP agonists interact with buprenorphine in a synergistic manner to produce antinociceptive effects (25). Simultaneous activation of both NOP and MOP receptors to a small degree may produce desirable analgesic effects with fewer side effects-that is, a wider therapeutic window (17).…”

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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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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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Section: Discussioncontrasting

confidence: 50%

mentioning

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.

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102

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“…In the same group of subjects, systemic NOP agonists produced antinociception without such side effects, but caused sedation at a dose that was approximately 30-fold higher than the full antinociceptive doses. 52,84,92 These results indicate that NOP agonists have a much wider therapeutic window compared with MOP agonists in primates. In particular, lack of respiratory depression of NOP agonists are expected to be much safer than the use of MOP agonists.…”

Section: ■ Effects Of Systemic Nop-related Ligandsmentioning

confidence: 83%

“…52,89 In a newly developed primate model of inflammatory pain, MOP agonists, NSAIDs, and NOP agonists were equally effective in inhibiting carrageenan-induced allodynia/hyperalgesia. 37,89 Equal effectiveness of MOP and NOP agonists across different primate pain models are very promising.…”

Section: ■ Effects Of Systemic Nop-related Ligandsmentioning

confidence: 99%

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

Lin

2012

ACS Chem. Neurosci.

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Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/ orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans.

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“…1,2 We have recently reported the discovery of a series of small molecules, characterized by their high NOP and opioid receptor agonistic activity. 3 This series included uncyclized (e.g., 1) as well as spirocyclic examples (e.g., 2a).…”

mentioning

confidence: 99%

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

Schunk

Linz

Hinze

et al. 2014

ACS Med. Chem. Lett.

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In a previous communication, our efforts leading from 1 to the identification of spiro [cyclohexanedihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6′-, which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain. KEYWORDS: NOP receptor agonists, MOP receptor agonists, cebranopadol, analgesics R ecent publications indicate that small molecules activating both nociceptin/orphanin FQ peptide (NOP) and mu opioid peptide (MOP) receptors may potentiate opiate analgesia and at the same time display an improved side effects profile. 1,2 We have recently reported the discovery of a series of small molecules, characterized by their high NOP and opioid receptor agonistic activity. 3 This series included uncyclized (e.g., 1) as well as spirocyclic examples (e.g., 2a). The discovery of spirocyclic 2a originated from the respective uncyclized analogues, which were potent NOP and MOP receptor binders but sometimes hampered by only partial agonistic NOP and MOP receptor activity. In particular, the spiroindole derivates sparked our interest due to their structural novelty and favorable in vitro and in vivo properties. The leading spiroether 2a exhibited strong efficacy in preclinical models of acute (ED 50 rat tail-flick: 3.63 nmol/kg i.v.) and neuropathic pain (ED 50 rat spinal nerve ligation: 1.05 nmol/kg i.v.) but was hampered by poor pharmacokinetic (PK) properties in rats with high clearance, large volume of distribution, moderate half-life (Cl = 4.0 L/h·kg; V ss = 7.52 L/kg; t 1/2 = 1.6 h), and a critically very low oral bioavailability (F = 4%).We herein report our efforts to further optimize the spiroindole lead 2a, which eventually led to the discovery of trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro-[cyclohexane-1,1′(3′H)-pyrano [3,4-b]indol]-4-amine (3a, cebranopadol), a novel potent analgesic NOP and opioid receptor agonist, currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.The structure−activity relationship (SAR) established around the uncyclized scaffolds (e.g., 1) suggested that a broad variety of linkers such as alcohols, ethers, and amines are tolerated, showing high NOP and MOP receptor binding affinities. 3 As a result, we applied this knowledge through analogous structural variations to lead structure 2a (region A, Figure 1). These changes were also combined with a targeted approach to improve the poor PK profile, in particular by addressing metabolically liable regions B and C.With this in mind, the transformation of the oxacyclic spiro moiety into a carba-, aza-, or thio-cyclic moiety was investigated. Advancing from the oxacyclic spiro 2a to the azacyclic moiety 5a led to equally potent NOP and MOP receptor binders, as well as the introduction of the N-methyl subunit 6a. Similarly, pot...

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Roles of μ-Opioid Receptors and Nociceptin/Orphanin FQ Peptide Receptors in Buprenorphine-Induced Physiological Responses in Primates

Cited by 92 publications

References 38 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

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

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