Receptor Pharmacology Flashcards
So came up with the ternary complex model?
De lean (1980)
What is the ternary complex model?
A+R<=>AR+G
“ “
A+RG<=>ARG
RG = preformed receptor G protein complex
What occurs to ligand affinity with out with the presence of GTP?
In the presence of GPP (GTP analog) will be low affinity because G proteins are activated therefore no preformed RG complex
Without GPP there is high affinity as RG complex is formed
Why without GTP is the displacement curve hill slope change with increasing agonist?
Slope is less steep because affinity for agonist changes
Initially will bind to preformed RG complexes (high affinity) but there are no enough G proteins to form a preformed RG complex on every receptor (R = low affinity state)
What can we infer from inverse agonists?
Some receptors have constitutive activity without a bound agonist
Therefore receptors can exist in an R (inactive) or R* (active) state
On a graph measuring GTPase activity against Log(ligand) for a mew opioids receptor what does it look like on addition of :
DADLE (full agonist)
MR2266 (antagonist)
Naloxone (inverse agonist)
DADLE (full agonist) = dose responce curve
MR2266 (antagonist) - straight line
Naloxone (inverse agonist) = decrease in GTPase activity
What does that fact naloxone decreases GTPase activity mean?
There must be a basal level of GTPase activity even without an agonist
What percentage of anatagonists were actuall shown to be inverse agonists?
Approx 80%
What residue is imporant to prevent constitutive activity of a1AR?
The alanine at 293 (WT) regulates constitutive activity as mutagenesis studies here increase constitutive activity
Alanine 293 keeps it in the R state and prevents conversion to R*
What is the extended ternary complex model?
AR<=>AR<=>ARG
“ “ “
R <=> R* <=> R*G
ARG and RG = response
What state does a full agonist stabilise?
R*»R
What state does a partial agonist stabilise?
R*>R
What state does an antagonist stabilise?
R*= R
Preserved equilibrium between R and R* therefore no net conformational change
What state does an inverse agonist stabilise?
R
In a system where there is no constitutive activity what is the difference between adding a antagonist and inverse agonist?
No effect as no baseline R* activity to being with