Introduction to the phenomenon of Biased agonism with few examples of receptors exhibiting this phenomenon and an example of drug developed on the basis of biased agonism.
Deepak Pandey, PG Pharmacology, VMMC
2. OUTLINE
1. What is “Biased Agonism”?
2. Hypotheses for biased agonism
3. GPCRs and β-arrestin pathway
4. Enumeration of different GPCRs showing biased agonism and their
significance
5. Role of biased agonism in drug development
6. Oliceridine
7. Summary
3. Introduction
• A ligand binding to receptor may
be-
• Full Agonist/Agonist- Interacts with
receptor maximal response
• Partial agonists- Partial efficacy at
receptor relative to a full agonist
• Antagonist- Blocks the action
mediated through receptor no
response
• Inverse agonist- Induces
pharmacological response opposite to
that of agonist
4. Introduction
• Conventionally, response of
ligand- receptor interaction
presumed to be mediated
through single cascade of
molecules in specified
direction.
• Multiple downstream signaling
pathways found which mediate
their action through separate
sets of effector molecules and
second messengers.
5. Introduction
• Balanced agonist- Shows similar
intrinsic efficacy through either
pathway.
• Biased agonist- Shows more
intrinsic efficacy towards one
pathway as compared to the
other.
{Intrinsic efficacy is the relative
ability of a drug-receptor complex
to produce a maximum functional
response}
Here, Agonist in (A) is a balanced agonist while Agonist in (B) &
(C) are biased agonists.
6. Introduction
• Biased Agonism- The phenomenon
where downstream signalling and
response mediated through a
receptor varies with different
ligands.
• Also known as- Functional
selectivity, Stimulus trafficking,
Functional dislocation, Biased
signaling, Differential engagement
or Ligand-directed signaling
• It is mostly seen in GPCRs but has
also been observed in other
receptors
Here, The same receptor while binding to three different ligands
L1, L2 & L3 activates different pathways
7. HYPOTHESIS FOR BIASED AGONISM
• Biomolecular interaction b/w ligand &
receptor specific conformation of
receptor favour binding to a specific
molecule (Barcode hypothesis)1
• The quantitative ratio of G-protein, β-
arrestin & other signalling protein
varies with different location of same
receptor(System Bias)2
• The quantitative ratio varies according
to different physiological, pathological
factors(Dynamic Bias)3
• Relative affinity of effector molecules
for the receptor1
References-
1. Kenakin T (2015a) The effective application of biased signaling to new drug discovery. Mol Pharmacol 88(6): 1055‐1061.
2. Onfroy L, Galandrin S, Pontier SM, Seguelas M‐H, N’Guyen D, Sénard J‐M and Galés C (2017) G protein stoichiometry dictates biased agonism through distinct
receptor‐G protein partitioning. Sci Rep 7(1): 7885
3. Michel MC, Seifert R and Bond RA (2014) Dynamic bias and its implications for GPCR drug discovery. Nature Reviews Drug Discovery 13(11): 869‐870.
8. GPCRs & Biased Agonism
• Earlier assumed to exist in 2 states acted like
switch and turn on/ turn off mechanism
• Recently, found to exist in multiple states of
distinct conformations influenced by both
ligands and bound effector proteins
• The signalling pathway is either G-protein
dependent or G-protein independent pathway/
β-arrestin pathway
• G-protein dependent pathway- heterotrimeric
proteins;
• GPCR activation secondary messengers
cAMP, IP3, DAG
• G-protein independent pathway/β-arrestin
dependent signalling pathway-
• GPCR activation G-protein coupled receptor
kinase(GRK) phosphorylate intracellular domain
of GPCR recruit β-arrestin
9. GPCR & Biased Agonism
β-arrestin recruitment mediates-
• Desensitization of GPCR
signalling and internalization
of receptor
• Activation of MAPK (Mitogen
activated protein kinase)i.e,
ERK (extracellular receptor
kinases)
10. GPCR & Biased Agonism
• Different ligands mediate their respective action on GPCR through a combination
of both pathways
• Biased agonist- Have more intrinsic efficacy towards one pathway-
• G-protein dependent pathway- G-protein biased agonists
• β-arrestin pathway- β-arrestin biased agonists
12. Receptors G-protein dependent
pathway
β-arrestin pathway Drug Development
β Adrenergic receptor Metoprolol, Alprenolol &
Carvedilol- Cardiac
fibrosis & Impaired
diastolic function
Developing Antagonists
with lesser intrinsic
efficacy for β-arrestin
recruitment to reduce
these side effects
Angiotensin II type I
receptor
TRV120027- Increased
cardiac performance &
preserved stroke volume
compared to other ARBs.
Developing ARBs with
agonistic activity towards
β-arrestin pathway
μ opioid receptor Analgesic effect Constipation, respiratory
depression, tolerance,
dysphoria
Developing analgesics
biased towards G-protein
dependent pathway
Dopamine (D2) receptor Antipsychotic properties
through β-arrestin
agonism
Developing D2 receptor
antagonist with intrinsic
activity towards β-arrestin
recruitment
13. Receptors G-protein dependent
pathway
β-arrestin pathway Drug Development
Apelin J receptors Increased myocardial
contractility &
vasodilation
Mechanical stretch
stimulates β-arrestin
pathway Cardiac
hypertrophy
Cardioprotective drugs for
CHF biased towards G-
protein dependent
pathway
GLP-1 receptors Promote β-cell
proliferation & protection
from apoptosis
Discovery of β-arrestin
biased agonists
potential therapeutics for
diabetes
14. Role of Biased agonism in Drug development
• Design pathway selective ligands
• Allows targeted modulation of cellular function
• Reduced side effects or undesired outcomes
• Quantification of ligand bias for selection of candidate compounds for
drug development
• Measuring specific indicators of second messenger production of each
pathway and comparing their concentration in cell-based assays e.g,
monitoring production of cAMP or phosphorylation of ERK 1/2
• Studying direct G-protein coupling and activation
15. Oliceridine (TRV 130)
• Recently approved by FDA in Aug 2020 for short term pain
management.
• In an animal study by Trevena-
• β-arrestin2 knock out mice and rats injected with β-arrestin interfering RNAs-
Enhanced analgesia compared to morphine with less tolerance and little
respiratory suppression.
• Led to hypothesis- µ-Opioid receptor is a biased agonist
• Analgesic effect of µ-Opioid receptor is due to G-protein dependent pathway
• Constipation & Respiratory depression- due to β-arrestin pathway
16. Oliceridine (TRV 130)
• Compound TRV 130 (Oliceridine) developed through computational
docking
• Reported to be similar to morphine in efficacy through G- protein
dependent pathway but less β-arrestin recruitment activity fewer
reported side effects compared with morphine
• Challenges-
• Data derived from computational docking- different and difficult to apply in
real scenario
• The overall clinical outcome of drug may differ when used in long run
17. Summary-
• Biased agonism is an emerging concept which has changed the way
ligands-receptors interactions are studied
• It has explained different clinical responses and effects of few drugs
• It holds promise for development of targeted drugs
• Most of the conclusions are presumptive and further studies are
required to validate the same.
