Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and...

Full description

Bibliographic Details
Main Authors: Joaquim Azevedo Neto, Anna Costanzini, Roberto De Giorgio, David G. Lambert, Chiara Ruzza, Girolamo Calò
Format: Article
Language:English
Published: MDPI AG 2020-08-01
Series:Molecules
Subjects:
Online Access:https://www.mdpi.com/1420-3049/25/17/3870
_version_ 1827707622090866688
author Joaquim Azevedo Neto
Anna Costanzini
Roberto De Giorgio
David G. Lambert
Chiara Ruzza
Girolamo Calò
author_facet Joaquim Azevedo Neto
Anna Costanzini
Roberto De Giorgio
David G. Lambert
Chiara Ruzza
Girolamo Calò
author_sort Joaquim Azevedo Neto
collection DOAJ
description Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.
first_indexed 2024-03-10T16:50:06Z
format Article
id doaj.art-c2d177aea22a4257af176aa2c994171b
institution Directory Open Access Journal
issn 1420-3049
language English
last_indexed 2024-03-10T16:50:06Z
publishDate 2020-08-01
publisher MDPI AG
record_format Article
series Molecules
spelling doaj.art-c2d177aea22a4257af176aa2c994171b2023-11-20T11:21:09ZengMDPI AGMolecules1420-30492020-08-012517387010.3390/molecules25173870Biased versus Partial Agonism in the Search for Safer Opioid AnalgesicsJoaquim Azevedo Neto0Anna Costanzini1Roberto De Giorgio2David G. Lambert3Chiara Ruzza4Girolamo Calò5Department of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, ItalyDepartment of Morphology, Surgery, Experimental Medicine, University of Ferrara, 44121 Ferrara, ItalyDepartment of Morphology, Surgery, Experimental Medicine, University of Ferrara, 44121 Ferrara, ItalyDepartment of Cardiovascular Sciences, Anesthesia, Critical Care and Pain Management, University of Leicester, Leicester LE1 7RH, UKDepartment of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, ItalyDepartment of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, ItalyOpioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.https://www.mdpi.com/1420-3049/25/17/3870opioidsmu receptoranalgesiaopioid side effectsbiased agonismpartial agonism
spellingShingle Joaquim Azevedo Neto
Anna Costanzini
Roberto De Giorgio
David G. Lambert
Chiara Ruzza
Girolamo Calò
Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
Molecules
opioids
mu receptor
analgesia
opioid side effects
biased agonism
partial agonism
title Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
title_full Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
title_fullStr Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
title_full_unstemmed Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
title_short Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
title_sort biased versus partial agonism in the search for safer opioid analgesics
topic opioids
mu receptor
analgesia
opioid side effects
biased agonism
partial agonism
url https://www.mdpi.com/1420-3049/25/17/3870
work_keys_str_mv AT joaquimazevedoneto biasedversuspartialagonisminthesearchforsaferopioidanalgesics
AT annacostanzini biasedversuspartialagonisminthesearchforsaferopioidanalgesics
AT robertodegiorgio biasedversuspartialagonisminthesearchforsaferopioidanalgesics
AT davidglambert biasedversuspartialagonisminthesearchforsaferopioidanalgesics
AT chiararuzza biasedversuspartialagonisminthesearchforsaferopioidanalgesics
AT girolamocalo biasedversuspartialagonisminthesearchforsaferopioidanalgesics