Characterisation of Agonist-Receptor Interaction: Occupancy, Affinity, Dose-Response Curve, Potency, Efficacy

Question 1

Types of Receptor Ligands

Answer 1

Agonist
Full Agonist: can evoke maximal effect
Partial Agonist: evokes submaximal effect

Antagonist

Allosteric Modulator

Inverse Agonist

Question 2

‘Equation’ of Agonist Action

Answer 2

Agonist + Free Receptor Agonist Receptor Complex

Agonist Receptor Complex –> Activated Agonist-R Comp.

Activated Agonist-R Complex–> Effect

Question 3

Concentration- Occupancy Relationship

Answer 3

Agonist + Free Receptor Agonist Receptor Complex

Question 4

Definition of Occupancy

Answer 4

Fraction or percentage of receptors occupied by agonist

Question 5

Hill Langmuir Equation

Answer 5

p= Nl/Nt = c/ (c+(k2/k1)) = c/ (c+Kd)

p= Receptor occupancy
Nl= # Ligand Bound Rs
Nt= total # receptors

c= ligand conc
k2= Rate constant for dissociation
k1= Rate constant for association 

Kd= equilibrium dissociation constant of agonist-R compl.
Ligand conc. causing 50% occupancy

Question 6

Conclusions based on the Hill Langmuir Equation

Answer 6

Occupancy depends on
Ligand concentration and Kd

With high ligand concentrations occupancy approaches 1
Ergo: Ligand binding is saturable

Question 7

Graphical form of Hill Langmuir Equation

Answer 7

Sigmoid shaped using log scale
(hyperbola in normal conc scale)
Y Axis: Occupancy (%)
X Axis: log Conc

Turning point of sigmoid shape: Kd: 50% occupancy

Question 8

Kd

Answer 8

Characterises binding tendency of ligand–> affinity
Inversely proportional: Increase Kd, decrease affinity

High affinity-> high selectivity
Ligand binds to target R at low conc
Fewer SEs

EC50: Agonist conc. evoking 50%
Characterises potency of drug

Question 9

Concentration- Response Curves

Full Agonists
Partial Agonist with IA=0.5
Antagonist

Answer 9

Full Agonists reach 100% Effect; full height sigmoid
Middle part near linear

Partial Agonist with IA=0.5 (can be between 0 and 1)
Only reaches 50% Effect; half sized sigmoid
Less steep–> larger margin of safety

Antagonist
Line at bottom; doesn’t reach any effect

Potency Rank:
A, B> C

C will require higher dose for still lower effect

Question 10

Parameters of Concentration- Response Curve

Answer 10

Maximum of curve= efficacy
Expressed by IA
Clinical sig: determines how severe symp/ diseases
can be treated.
More severe–> need more efficacious drug

Position of curve along conc/dose axis: Potency
   Conc/dose req to induce given effect
   Drug needing lower conc is more potent
   EC 50 (conc) or ED50 (dose)
   Determines dosing: less potent-> higher conc needed

Slope of near-linear middle part of curve
Indicated how large increase of effect prod. by
increasing conc.
Related to margin of safety: steeper- smaller margin

Question 11

Affinity
Potency
Efficacy
Intrinsic Activity

Answer 11

Affinity
Binding tendency of a ligand
Inversely proportional to Kd
Can only be compared when drugs bind same R

Potency
Conc. of dose req to induce given effect
Lower dose-> higher potency; characterised by ED50
Dep on affinity, signal amplification, R density, intrinsic
efficacy

Efficacy
Max of curve, max effect provoked by drug
Expressed by IA
Dep on intrinsic efficacy, signal amplification, R density

Intrinsic Activity
(Max Effect Inducible by drug) / (max effect possible in
given tissue)
Range 0-1

Question 12

Receptor Reserve

Answer 12

Max effect that can be elicited with submaximal R occupancy: R reserve is fraction of Rs that are apparently not req for maximal effect

May be due to
High signal amplification during signal transduction
High R density
(High intrinsic efficacy of agonist)

Receptor downreg doesn’t decrease max. effect of full agonist (until certain limit)

Question 13

Effect of R down-regulation on full agonist

Answer 13

Decrease in potency and efficacy

Sigmoid curve decreases in size and shifts to right (need higher concentration)

Question 14

Intrinsic Efficacy

Answer 14

Describes receptor activating ability/ power of agonist

Describes how efficiently R occupancy translates into effect

Higher intrinsic efficacy-> increase efficacy until max possible effect of tissue reached
After: appearance and increase in receptor reserve

On curve:
Increased intrinsic efficacy-> shift to the left

Unlike IA: doesn’t have upper value: suitable to distinguish between R activating abilities of full agonists

Question 15

Factors determining effect of an agonist

Answer 15

Number of activated Rs

Intrinsic efficacy

Question 16

Agonist specific parameters

Answer 16

Agonist conc
Affinity (Kd)
Intrinsic efficacy

Question 17

Tissue specific parameters

Answer 17

Receptor density

Signaling amplification