GPCRs biased agonism Flashcards
What is biased agonism?
It is where different agonists acting at the same receptor can stabilise distinct conformations that differentially engage downstream effectors.
Could be manipulated if certain signalling pathways are associated with side effects.
Difficult to identify due to differences in different assays, based on signal amplification, receptor reserve, and assay sensitivity.
Example of AT1 biased agonism and implications
Angiotensin II is seen to activate Gaq signalling, whereas SII-angiotensin does not.
SII-angiotensin and angiotensin II do however signal through B-arrestin - phosphorylation of ERK.
Both AngII and SII use shortening of isolated cardiomyocytes. This effect was prevented by knockout of B-arrestin2, but not B-arrestin1 in SII. This knockout did not change the effect of AngII on cardiomyocytes.
Further evidence that SII signals specifically through B-arrestin2.
The Gaq signalling pathway is associated with Na+/fluid retention. As such, selectively targeting the B-arrestin pathway could have potential at reducing side effects.
Example and outcome of AT1R biased agonist development
TRV120027 was created to have potent selectivity for the B-arrestin pathway. Was also found to inhibit the Gaq-signalling of AT1R mediated by angiotensin II.
While early trials showed some promising results, in clinical trials it ended up not having significant effects compared to placebo.
What are siRNA?
Small interfering RNA is a tool used for silencing protein coding genes.
It is synthetic, and designed to specifically target a particular mRNA for degradation.
Once in the cell, it is incorporated into other proteins - forms RNA-inducing silencing complex (RISC). Once this occurs, the siRNA is unwound to form single stranded siRNA. once this occurs it can bind to complementary mRNA and cleave it. The cell then degrades the cleaved mRNA.
Where are the opioid receptors found and what are their roles
Brain: pain, emotion, reward, addiction
Brainstem: respiratory control (as such can be used as an antitussive)
Spine: inhibiting pain transmission
peripheral neurones: pain sensation
intestine: peristalsis
Biased agonism of MOP and potential uses
There was a hypothesis that suggested that side effects are mediated through B-arrestin pathways. respiratory depression, constipation, dependence, withdrawal, and tolerance suggested to be mediated by B-arrestin
Could be exploited for safer analgesics.
Newer research has identified that there is no evidence of biased agonism at the MOP with current ligands.
Correlation of efficacy and therapeutic window in opioids
Low efficacy drugs such as buprenorphine have a larger therapeutic window than the high potency opioids: fentanyl.
Therapeutic window negatively correlates to intrinsic efficacy
How biased agonism is identified experimentally
Utilises operational models of agonism.
Tau represents the [receptors] and the efficiency of coupling.
Look at the each pathway (e.g., with BRET) and quantify the Tau of the drug at that signalling pathway.
As such, each drug will have their own Tau/KA ratio for each signalling pathway.
Then the differences between these Tau can be normalised as a way to quantify the pathway bias.
