Biased versus Partial Agonism in the Search for Safer Opioid Analgesics.
Joaquim Azevedo NetoAnna CostanziniRoberto De GiorgioDavid G LambertChiara RuzzaGirolamo CalòPublished in: Molecules (Basel, Switzerland) (2020)
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.
Keyphrases
- pain management
- chronic pain
- electronic health record
- big data
- drug discovery
- postoperative pain
- genome wide
- drug induced
- healthcare
- stem cells
- magnetic resonance imaging
- gene expression
- cell therapy
- early onset
- irritable bowel syndrome
- high dose
- data analysis
- diffusion weighted imaging
- ultrasound guided
- dna methylation
- bone marrow
- sleep quality
- type diabetes
- nucleic acid
- physical activity
- high intensity
- diabetic rats
- transcription factor
- replacement therapy
- contrast enhanced