Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

2008 ◽  
Author(s):  
Mei-Chuan Ko
Keyword(s):  
Nop Receptor ◽  
Receptor Agonists ◽  
Pharmacological Studies

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

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 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.

Rapid access towards follow-up NOP receptor agonists using a knowledge based approach

2009 ◽  
Vol 19 (22) ◽  
pp. 6441-6446 ◽  
Author(s):  
Ronald Palin ◽  
John K. Clark ◽  
Louise Evans ◽  
Helen Feilden ◽  
Dan Fletcher ◽  
...  
Keyword(s):  
Nop Receptor ◽  
Receptor Agonists ◽  
Rapid Access ◽  
Knowledge Based

scholarly journals Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists

2019 ◽  
Vol 12 (574) ◽  
pp. eaau8072 ◽  
Author(s):  
Anika Mann ◽  
Lionel Moulédous ◽  
Carine Froment ◽  
Patrick R. O’Neill ◽  
Pooja Dasgupta ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Receptor Phosphorylation ◽  
Receptor Agonists ◽  
Differential Signaling ◽  
Receptor Family

Agonists of the nociceptin/orphanin FQ opioid peptide (NOP) receptor, a member of the opioid receptor family, are under active investigation as novel analgesics, but their modes of signaling are less well characterized than those of other members of the opioid receptor family. Therefore, we investigated whether different NOP receptor ligands showed differential signaling or functional selectivity at the NOP receptor. Using newly developed phosphosite-specific antibodies to the NOP receptor, we found that agonist-induced NOP receptor phosphorylation occurred primarily at four carboxyl-terminal serine (Ser) and threonine (Thr) residues, namely, Ser346, Ser351, Thr362, and Ser363, and proceeded with a temporal hierarchy, with Ser346 as the first site of phosphorylation. G protein–coupled receptor kinases 2 and 3 (GRK2/3) cooperated during agonist-induced phosphorylation, which, in turn, facilitated NOP receptor desensitization and internalization. A comparison of structurally distinct NOP receptor agonists revealed dissociation in functional efficacies between G protein–dependent signaling and receptor phosphorylation. Furthermore, in NOP-eGFP and NOP-eYFP mice, NOP receptor agonists induced multisite phosphorylation and internalization in a dose-dependent and agonist-selective manner that could be blocked by specific antagonists. Our study provides new tools to study ligand-activated NOP receptor signaling in vitro and in vivo. Differential agonist-selective NOP receptor phosphorylation by chemically diverse NOP receptor agonists suggests that differential signaling by NOP receptor agonists may play a role in NOP receptor ligand pharmacology.

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