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

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 well-honed 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 abuse-free opioid analgesics.

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Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200508082615 ◽

2020 ◽

Vol 20 (31) ◽

pp. 2878-2888 ◽

Cited By ~ 2

Author(s):

Norikazu Kiguchi ◽

Huiping Ding ◽

Shiroh Kishioka ◽

Mei-Chuan Ko

Keyword(s):

Opioid Receptor ◽

Receptor Agonist ◽

Physical Dependence ◽

Opioid Peptide ◽

Receptor Activation ◽

Abuse Liability ◽

Similar Distribution ◽

Nop Receptor ◽

Orphanin Fq ◽

Receptor Agonists

Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

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Herbal Preparations of Medical Cannabis: A Vademecum for Prescribing Doctors

Medicina ◽

10.3390/medicina56050237 ◽

2020 ◽

Vol 56 (5) ◽

pp. 237 ◽

Cited By ~ 8

Author(s):

Pietro Brunetti ◽

Simona Pichini ◽

Roberta Pacifici ◽

Francesco Paolo Busardò ◽

Alessandro del Rio

Keyword(s):

Therapeutic Potential ◽

Scientific Evidence ◽

Abuse Liability ◽

Medical Cannabis ◽

Preparation Methods ◽

Herbal Preparations ◽

Routes Of Administration ◽

International Agencies ◽

Medical Indications ◽

Different Sources

Cannabis has been used for centuries for therapeutic purposes. In the last century, the plant was demonized due to its high abuse liability and supposedly insufficient health benefits. However, recent decriminalization policies and new scientific evidence have increased the interest in cannabis therapeutic potential of cannabis and paved the way for the release of marketing authorizations for cannabis-based products. Although several synthetic and standardized products are currently available on the market, patients’ preferences lean towards herbal preparations, because they are easy to handle and self-administer. A literature search was conducted on multidisciplinary research databases and international agencies or institutional websites. Despite the growing popularity of medical cannabis, little data is available on the chemical composition and preparation methods of medical cannabis extracts. The authors hereby report the most common cannabis preparations, presenting their medical indications, routes of administration and recommended dosages. A practical and helpful guide for prescribing doctors is provided, including suggested posology, titration strategies and cannabinoid amounts in herbal preparations obtained from different sources of medical cannabis.

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The Role of the Cannabinoid CB2 Receptor in Pain Transmission and Therapeutic Potential of Small Molecule CB2 Receptor Agonists

Current Medicinal Chemistry ◽

10.2174/092986707780363023 ◽

2007 ◽

Vol 14 (8) ◽

pp. 917-936 ◽

Cited By ~ 93

Author(s):

G Whiteside ◽

G. Lee ◽

K Valenzano

Keyword(s):

Small Molecule ◽

Therapeutic Potential ◽

Cb2 Receptor ◽

Receptor Agonists ◽

Pain Transmission

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Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential

Physiology ◽

10.1152/physiol.00030.2005 ◽

2005 ◽

Vol 20 (5) ◽

pp. 357-365 ◽

Cited By ~ 54

Author(s):

Elaine M Sinclair ◽

Daniel J. Drucker

Keyword(s):

Type 2 Diabetes ◽

Human Disease ◽

Clinical Relevance ◽

Therapeutic Potential ◽

Mechanisms Of Action ◽

Receptor Antagonists ◽

Glucagon Receptor ◽

Receptor Agonists ◽

Glucagon Like Peptide

Glucagon is used for the treatment of hypoglycemia, and glucagon receptor antagonists are under development for the treatment of type 2 diabetes. Moreover, glucagon-like peptide (GLP)-1 and GLP-2 receptor agonists appear to be promising therapies for the treatment of type 2 diabetes and intestinal disorders, respectively. This review discusses the physiological, pharmacological, and therapeutic actions of the proglucagon-derived peptides, with an emphasis on clinical relevance of the peptides for the treatment of human disease.

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Therapeutic potential of nuclear receptor agonists in Alzheimer’s disease

The Journal of Lipid Research ◽

10.1194/jlr.r075556 ◽

2017 ◽

Vol 58 (10) ◽

pp. 1937-1949 ◽

Cited By ~ 32

Author(s):

Miguel Moutinho ◽

Gary E. Landreth

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nuclear Receptor ◽

Therapeutic Potential ◽

Receptor Agonists

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How glucagon-like peptide 1 receptor agonists work

Endocrine Connections ◽

10.1530/ec-21-0130 ◽

2021 ◽

Author(s):

Christine Rode Andreasen ◽

Andreas Andersen ◽

Filip Krag Knop ◽

Tina Vilsbøll

Keyword(s):

Body Weight ◽

Therapeutic Potential ◽

Clinical Effects ◽

Glucose Lowering ◽

Receptor Agonists ◽

Reduce Body Weight ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Clinical Utilisation

Recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of actions, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

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