Cardiovascular and renal effects of novel non‐peptide nociceptin opioid peptide (NOP) receptor agonists

2021 ◽  
Author(s):  
Ian B. Denys ◽  
Juan Gao ◽  
Jane C. Sutphen ◽  
Nurulain T. Zaveri ◽  
Daniel R. Kapusta
Keyword(s):  
Opioid Peptide ◽  
Nop Receptor ◽  
Renal Effects ◽  
Receptor Agonists

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

2020 ◽  
Vol 20 (31) ◽  
pp. 2878-2888 ◽  
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.

Structure-Based SAR in the Design of Selective or Bifunctional Nociceptin (NOP) Receptor Agonists

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Michael E. Meyer ◽  
Arpit Doshi ◽  
Dennis Yasuda ◽  
Nurulain T. Zaveri
Keyword(s):  
Nop Receptor ◽  
Receptor Agonists

Renal effects of selective adenosine receptor agonists in anesthetized rats

1987 ◽  
Vol 252 (2) ◽  
pp. F299-F303 ◽  
Author(s):  
P. C. Churchill ◽  
A. Bidani
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Adenosine Receptor ◽  
Renin Secretion ◽  
Renal Effects ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Arterial Blood ◽  
Selective Agonist

Exogenous adenosine affects renal hemodynamics, renal tubular transport processes, and the secretion of renin. However, adenosine is not a selective agonist; it activates both A1 and A2 cell-surface receptors and it binds to an intracellular P-site that inhibits adenylate cyclase activity. Recent in vitro studies have suggested that activation of A1- and A2- adenosine receptors results in opposite effects on renin secretion. The purpose of these experiments was to examine the renal effects of A1- and A2-adenosine receptor agonists in vivo. 5'-N-ethylcarboxamide adenosine (NECA), 2-chloroadenosine (2-CLA), and N6-cyclohexyladenosine (CHA) were infused intravenously at rates that produced comparable decreases in systemic arterial blood pressure. All three of these adenosine analogues produced comparable decreases in para-aminohippurate (PAH) and inulin clearances and in Na and K excretion rates. CHA, an A1-selective agonist, markedly decreased plasma renin concentration (PRC), whereas NECA, an A2-selective agonist, markedly increased PRC; 2-CLA, a nonselective agonist, produced a smaller increase in PRC. Taken together, these results suggest that occupation of A1- and A2-receptors inhibits and stimulates renin secretion in vivo, independently of the effects of these adenosine receptor agonists on arterial blood pressure, renal hemodynamics, and tubular Na and K transport.

Structure–activity relationships and CoMFA of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic properties

2008 ◽  
Vol 16 (6) ◽  
pp. 2829-2851 ◽  
Author(s):  
Ronald Palin ◽  
John K. Clark ◽  
Louise Evans ◽  
Andrea K. Houghton ◽  
Philip S. Jones ◽  
...  
Keyword(s):  
Nop Receptor ◽  
Structure Activity Relationships ◽  
Receptor Agonists ◽  
Structure Activity

scholarly journals Biased Opioid Ligands

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4257 ◽  
Author(s):  
Abdelfattah Faouzi ◽  
Balazs R. Varga ◽  
Susruta Majumdar
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Signal Transduction Pathway ◽  
Opioid Peptide ◽  
Nop Receptor ◽  
Biased Agonism ◽  
Opioid Ligands ◽  
Substance Abuse Disorders ◽  
Δ Opioid Receptor

Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

2010 ◽  
Author(s):  
Mei-Chuan Ko
Keyword(s):  
Nop Receptor ◽  
Receptor Agonists ◽  
Pharmacological Studies

scholarly journals Central nociceptin/orphanin FQ system elevates food consumption by both increasing energy intake and reducing aversive responsiveness

2010 ◽  
Vol 299 (2) ◽  
pp. R655-R663 ◽  
Author(s):  
Pawel K. Olszewski ◽  
Martha K. Grace ◽  
Shahrzad Shirazi Fard ◽  
Madeleine Le Grevès ◽  
Anica Klockars ◽  
...  
Keyword(s):  
Energy Intake ◽  
Low Dose ◽  
Opioid Peptide ◽  
Central Nucleus ◽  
Mrna Levels ◽  
Solitary Tract ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Receptor Ligand ◽  
Anorexigenic Effect

Nociceptin/orphanin FQ (N/OFQ), the nociceptin opioid peptide (NOP) receptor ligand, increases feeding when injected centrally. Initial data suggest that N/OFQ blocks the development of a conditioned taste aversion (CTA). The current project further characterized the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodology. We determined that the same low dose of the NOP antagonist [Nphe1]N/OFQ(1-13)NH2 delivered via the lateral ventricle diminishes both N/OFQ- and deprivation-induced feeding. This anorexigenic effect did not stem from aversive consequences, as the antagonist did not cause the development of a CTA. When [Nphe1]N/OFQ(1-13)NH2 was administered with LiCl, it moderately delayed extinction of the LiCl-induced CTA. Injection of LiCl + antagonist compared with LiCl alone generated an increase in c-Fos immunoreactivity in the central nucleus of the amygdala. The antagonist alone elevated Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, and central nucleus of the amygdala. Hypothalamic NOP mRNA levels were decreased during energy intake restriction induced by aversion, as well as in non-CTA rats food-restricted to match CTA-reduced consumption. Brain stem NOP was upregulated only in aversion. Prepro-N/OFQ mRNA showed a trend toward upregulation in restricted rats ( P = 0.068). We conclude that the N/OFQ system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially tainted food.

Nociceptin and its metabolite attenuate U0126-induced memory impairment through a nociceptin opioid peptide (NOP) receptor-independent mechanism

2010 ◽  
Vol 93 (3) ◽  
pp. 396-405 ◽  
Author(s):  
Masaya Miwa ◽  
Shogo Uchida ◽  
Fumika Horiba ◽  
Hiroshi Takeshima ◽  
Toshitaka Nabeshima ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Opioid Peptide ◽  
Nop Receptor ◽  
Independent Mechanism

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

2016 ◽  
Vol 113 (37) ◽  
pp. E5511-E5518 ◽  
Author(s):  
Huiping Ding ◽  
Paul W. Czoty ◽  
Norikazu Kiguchi ◽  
Gerta Cami-Kobeci ◽  
Devki D. Sukhtankar ◽  
...  
Keyword(s):  
Physical Dependence ◽  
Opioid Analgesic ◽  
Opioid Analgesics ◽  
Abuse Liability ◽  
Ratio Schedule ◽  
Tolerability Profile ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Self Administration ◽  
Receptor Agonists

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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