An example of a receptor

3D computer rendering of
the nicotinic acetylcholine
receptor.

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 Receptor Efficacy

An agonist is a ligand or drug that binds to specific receptors and

exerts some sort of functional effect after binding; i.e., it has efficacy
as well as affinity. It may mimic the effect of an endogenous
compound. A partial agonist only has partial efficacy even at 100%
receptor occupation; full agonists produce 100% of the possible effect.
But what exactly is a full agonist?

An antagonist at a receptor also displays affinity for that receptor but it

has no efficacy; i.e. it does not produce a functional effect after it
binds. Competitive antagonists compete with agonists for binding to
the same specific sites on receptors. They do not compete for non-
specific sites. Eg., atropine produces no functional effects on the
muscarinic subtype of acetylcholine receptors, but it blocks the effects
of acetylcholine on these receptors.
 Possible effects of drug on a receptor

1. Occupation theory - drug acts only as long as

it occupies the receptor (analogous to a sound
being emitted by an organ as long as the key
remains pressed).
2. Rate theory - drug action is proportional only
to the rate of combination between the drug
and the receptor (analogous to pressing a key
on a piano where sound is only emitted when
the key is first depressed).
Graphical depictions of
potency and efficacy

Drugs A & B clearly have

higher efficacy than drug C.
Drug A is more potent than
drug B.
You cannot assume that drug
A’s higher potency than drug
B is due to it having a higher
affinity of binding. This is a
classic error in assumption
since A could instead be
more efficacious than B (see
slide 8 later in this lecture).
The crux of the problem:
When you assay a receptor functionally, you relate drug
concentrations on the X-axis with receptor responses
on the Y-axis. But, how do you determine the relative
contributions of binding (affinity) and gating (efficacy)?

The del Castillo-Katz mechanism (1957)

binding gating

D+R 
 DR 
 DR*
A drug’s EC50 (a measure of its
potency) is NOT just dependent
on its binding affinity.
Separating affinity from efficacy: a very thorny problem

The del Castillo-Katz mechanism (1957)

Drug

D+R  DR 
  DR*

Unliganded Receptor Drug bound to Drug bound to

– no drug bound receptor – receptor in receptor – receptor in
inactive state active state
 Separating affinity from efficacy: a very thorny problem

k+1 
D+R  DR 
  DR*
k-1 

Receptor binding Receptor activation (gating)

k+1 - onset rate (binding) - transition rate to active state of receptor
k-1 - offset rate ( unbinding) - transition rate from active state of receptor
Binding affinity kd = k-1/k+1 Efficacy (E) = /
The likelihood that an individual receptor is found in the
active state (DR*) at any particular time in the presence
of a maximally-effective concentration of ligand:
p = E / (1 + E) p ranges from 0 to 1
Note that there is theoretically no upper bound on efficacy (getting
back to the question on the first slide of what exactly is a full
agonist).

In a functional study, the EC50 of a receptor’s

response is related to Kd and efficacy by the
equation
EC50 = Kd / (1 + E)
Thus, knowing the EC50 of a receptor’s response
to a drug provides you with no direct information
about the binding affinity of the drug. The EC50
(or K from lecture 9) is a function of both agonist
binding affinity as well as efficacy.
Why shifting drug response or binding curves to the left
or right may have nothing to do with binding affinity.

According to the equation EC50 = Kd / (1 + E) as efficacy approaches

zero, the EC50 approaches Kd. Thus, for compounds with no efficacy
(antagonists), their use in binding as well as functional assays reflects
their true affinities (Kd). This is not true for agonists.
Why does increasing efficacy leftshift binding and
response curves?

k+1 
D+R  DR 
  DR*
k-1 

Is there any reason to assume that the active form of the receptor
has the same affinity for drug as the inactive form? NO!
 Why does increasing efficacy leftshift binding and
response curves?
k+1 
D+R  DR 
  DR*
k-1 

Ty pe numbe rs into So lving fo r

this c o lumn
k+1 (binding o ns e t ra te ) nM-1 s -1 1.0 0 Affinity (nM) 1.0 0
k-1 (binding offs e t ra te ) s -1 1.0 0 Effic ac y (no units ) 1.0 0
b (s -1) 1.0 0 EC5 0 (nM) 0.5 0
a (s -1) 1.0 0 P (like liho od a s ingle re c e ptor is a c tiv e ) 0.5 0

Scenario 1. Assume k-1,  and  have a value of 1 s-1 and k+1 has a value
of 1 M-1 s-1.
Scenario 2. Assume k-1, and  have a value of 1 s-1 and k+1 has a value
of 1 M-1 s-1, but  has been increased to 100 s-1.

Scenario 3. Assume k-1, and  have a value of 1 s-1 and k+1 has a value of
1 M-1 s-1, but  has been decreased to 0.01 s-1.
So, can one possibly distinguish binding from gating?

Measure responses of single ion channels responding to different

concentrations of agonists that vary in efficacy and then fit those
activating (opening) / inactivating (closing) events to a kinetic model of
receptor function.

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Taurine is a partial agonist at the glycine receptor while glycine is

considered a full agonist (whatever that is!).