Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects

Zhu, Lianghan; Cui, Zhiying; Zhu, Qihua; Zha, Xiaoming; Xu, Yungen

doi:10.2174/1389557518666180716124336

Cited by 7 publications

(3 citation statements)

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“…These are potent μ-opioid agonists that exert addiction liability and numerous side effects, such as euphoria, addiction, respiratory depression, and gastrointestinal adverse reactions; therefore; circumventing these drawbacks is of extensive importance. A large amount of literature documented novel approaches to disconnecting the analgesic efficacy of μ-opioid agonists from morphine-like side effects, for example biasing the GPCRs over β-arrestin2 recruitment (TRV130, PZM21, HS665) or designing positive allosteric modulators of the MOR (BMS-986122), MOR inverse agonists/KOR antagonists [9], and multiple agonists of opioid receptors subtypes (SNC80, DPI-125) [10]. Different peptides and peptidomimetics have been reported in the literature to exert a strong antinociceptive effect on opioid receptors without involving the β-arrestin protein, which is thought to be responsible for respiratory depression and constipation associated with the use of naturally occurring and synthetic opioids.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

et al. 2019

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Morphine, oxycodone, fentanyl, and other µ-opioid receptors (MOR) agonists have been used for decades in antinociceptive therapies. However, these drugs are associated with numerous side effects, such as euphoria, addiction, respiratory depression, and adverse gastrointestinal reactions, thus, circumventing these drawbacks is of extensive importance. With the aim of identifying novel peptide ligands endowed with MOR inhibitory activity, we developed a virtual screening protocol, including receptor-based pharmacophore screening, docking studies, and molecular dynamics simulations, which was used to filter an in-house built virtual library of tetrapeptide ligands. The three top-scored compounds were synthesized and subjected to biological evaluation, revealing the identity of a hit compound (peptide 1) endowed with appreciable MOR inverse agonist effect and selectivity over δ-opioid receptors. These results confirmed the reliability of our computational approach and provided a promising starting point for the development of new potent MOR modulators.

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Section: Introductionmentioning

confidence: 99%

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

et al. 2019

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“…During the past decade efforts were made to develop effective multitarget opioid ligands as an alternative strategy to overcome the typical side effects associated with opioid selective agonists. − For instance, a valid analgesic effect with lower propensity to produce tolerance and physical dependence was reported for both dual MOR/DOR agonist − and MOR agonist/DOR antagonist ligands given in persistent pain models. − …”

mentioning

confidence: 99%

Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists

Pasquinucci

Parenti

Ruiz-Cantero

et al. 2020

ACS Med. Chem. Lett.

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Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonist LP1 resulted in retention of MOR affinity. Moreover, derivatives 7a, 7c, and 7d were biased MOR agonists toward ERK1,2 activity stimulation, whereas derivative 7e was a low potency MOR agonist on adenylate cyclase inhibition. They were further screened in the mouse tail flick test and PGE2-induced hyperalgesia and drug-induced gastrointestinal transit.

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“… 11 Previous studies have reported that opioids are effective in reducing pain during the awakening period; however, adverse effects such as pruritus, constipation, respiratory depression, and addiction are also likely. 12 Nalbuphine is a synthetic, mixed opioid and both an agonist of κ receptor and an antagonist of μ receptor. 13 It has good analgesic and sedative effects, mildly depresses the respiratory system, and is associated with good hemodynamic stability.…”

Section: Introductionmentioning

confidence: 99%

A Dose-Response Relationship Study of Prophylactic Nalbuphine to Reduce Pain During the Awakening Period in Patients Undergoing Laparoscopic Total Hysterectomy: A Randomized, Controlled, Double-Blind Clinical Study

Wang¹,

Wang²,

Zuo³

et al. 2022

DDDT

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Purpose Prophylactic intravenous nalbuphine was administered to observe its median effective dose (ED 50 ) in reducing pain after undergoing laparoscopic total hysterectomy. To investigate the effect of different doses of nalbuphine on postoperative analgesia and adverse reactions in patients. Patients and Methods The 120 patients undergoing laparoscopic total hysterectomy were divided into 6 groups: group C (control) and group P (5 different doses of nalbuphine) with 20 patients per group. The doses of nalbuphine in group P were in an equally proportional series (groups P1, P2, P3, P4, and P5 received doses of 0.280, 0.200, 0.140, 0.100, and 0.070 mg/kg, respectively), diluted to 20 mL with saline and administered 5 min before the induction of anesthesia. A similar volume (20 mL) of saline was administered to group C 5 min before the induction of anesthesia. The numeric rating scale (NRS) of patients during awakening and after surgery, the number of postoperative salvage analgesia, and the occurrence of postoperative adverse effects were recorded. Results The ED 50 (95% confidence interval (CI)) of nalbuphine in preventing pain during the awakening period in patients calculated using the point-slope method was 0.125 (0.108, 0.145) mg/kg. NRS scores differed among the 6 groups at 30 min and 1 h after extubation ( P < 0.001; P < 0.001). Pairwise comparisons between groups revealed that, at 30 min after extubation, compared with group P1, the NRS scores of groups P4, P5, and C were higher ( P = 0.001, P < 0.001, P < 0.001); compared with group P2, groups P5 and C had higher NRS scores ( P = 0.011, P = 0.001). At 1 h after extubation, the NRS scores of groups P1 and P2 were lower than that of group P4 ( P = 0.046, P = 0.036). Compared with the control, only the group P1 had a lower cough score ( P = 0.009) and there were no differences in the other groups. There were no differences in sedation score at 10 min after extubation, the incidence of adverse events at 24 h postoperatively, or the number of remedial analgesics at 24 h postoperatively ( P > 0.05). Conclusion The ED 50 (95% CI) of nalbuphine as a prophylactic in reducing pain during recovery was 0.125 (0.108, 0.145) mg/kg. Compared with the control, nalbuphine at doses of 0.140, 0.200, and 0.280 mg/kg prevented pain during the awakening period. Among these doses, 0.280 mg/kg was determined to be the best, the occurrence of cough was less during extubation and the postoperative analgesic effect was good. However, it is necessary to pay attention to the occurrence of adverse reactions. ...

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Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects

Cited by 7 publications

References 1 publication

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists

A Dose-Response Relationship Study of Prophylactic Nalbuphine to Reduce Pain During the Awakening Period in Patients Undergoing Laparoscopic Total Hysterectomy: A Randomized, Controlled, Double-Blind Clinical Study

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