The document discusses key concepts related to how ligands bind to proteins and receptors. It defines important terms like: 1) Equilibrium dissociation constant (Keq), which represents the concentration of ligand that occupies 50% of receptor sites. Keq is inversely related to affinity. 2) Potency, which refers to the concentration of a drug needed to produce a given effect. It is determined by receptor affinity. 3) Efficacy, which represents a drug's ability to induce a physiological response through a receptor. Full agonists elicit the maximum response while partial agonists have lower efficacy.

1. By: Dr. Vahid Nikoui
Email: nikoui@razi.tums.ac.ir

2. Ligands reside at a point of minimal energy within a
binding locus of a protein according to a ratio of the
rate that the ligand leaves the surface of the protein
(koff) and the rate it approaches the protein surface
(kon).
This ratio is the equilibrium dissociation constant of
the ligand–protein complex (denoted Keq = koff/kon)
and defines the molar concentration of the ligand in
the compartment containing the protein where 50%
of the protein has ligand bound to it at any one
instant.
The “affinity” or attraction of the ligand for the
protein is the reciprocal of Keq.

3. Association constant :
The ratio of the rate of onset of a molecule to a
receptor binding site and the rate of dissociation
of the molecule away from that site.

4. K1 :
Referring to the rate of onset of a molecule to a receptor.
k2 (k-1):
Referring to the rate of offset of a molecule from a receptor.
KA :
Standard pharmacologic convention for the equilibrium dissociation constant of an
agonist-receptor complex. It is the concentration that occupies half the receptor
population at equilibrium. It also can be thought of as the reciprocal of affinity.
KB :
Convention for the equilibrium dissociation constant of an antagonist-receptor
complex.
Kd:
Convention for the equilibrium dissociation constant of a radioligand-receptor
complex.
KI :
Basically the KB for an antagonist but specifically measured in a biochemical binding
study or enzyme assay.

7. Historically, this term was given to agonists to define
the property of the molecule that causes the
production of a physiological response.
However, with the discovery of negative efficacy
(inverse agonists) and efficacy related to other
properties of receptors that do not involve a
physiological response, a more general definition of
efficacy is that property of a molecule that causes the
receptor to change its behavior toward the host.
Efficacy (often called maximal efficacy), can be
measured with a graded dose-response curve but not
with a quantal dose-response curve.

9. Intrinsic efficacy:
A solely agonist-specific quantification of the ability
of the agonist to induce a physiological or
pharmacological response.
Thus, efficacy is the product of intrinsic efficacy
multiplied by the receptor density.
Negative efficacy :
Property of selective affinity of the molecule for the
inactive state of the receptor; this results in inverse
agonism.
Negative efficacy causes the active antagonism of
constitutive receptor activity but is observed only in
systems that have a measurably elevated basal
response due to constitutive activity.
It is a property of the molecule and not the system.

10. Potency :
The concentration (usually molar) of a drug that produces a
defined effect.
Often, potencies of agonists are defined in terms of EC50 or pEC50
values. The potency usually does not involve measures of
maximal effect but rather only in locations along the
concentration axis of dose response curves.
Potency is determined mainly by the affinity of the receptor for
the drug.
In graded dose-response measurements, the effect usually chosen
is 50% of the maximal effect ( EC50).
In quantal dose-response measurements ED50, TD50, and LD50 are
typical potency variables.
Potency can be determined from either graded (EC50) or quantal
dose-response curves (ED50, TD50, and LD50), but the numbers
obtained are not identical.
Potentiation :
The increase in effect produced by a molecule or procedure in a
pharmacological preparation.
This can be expressed as an apparent increase in efficacy (i.e.,
maximal response), potency, or both.

12. EC50/ED50 :
The “effective concentration” of an agonist producing (in this
case) 50% maximal response to that particular drug (not
necessarily 50% of the maximal response of the system).
ED50 is the in vivo counterpart of EC50 referring to the dose of
an agonist that produces 50% maximal effect.
Equiactive (equieffective) molar concentration (potency)
ratios (EMR, EPMR) :
Usually pertaining to agonists, these are the molar
concentrations that produce the same response in a given
system.
These ratios are dependent on the affinity and efficacy of the
agonists and thus are system independent, that is, characterize
agonists and receptors in all systems.
Care must be taken that the maximal responses of the agonists
concerned are equal.
Emax :
Conventional term for the maximal response capable of
being produced in a given system.

14. Selectivity :
The difference in activity a given biologically active
molecule has for two or more processes.
Thus, if a molecule has a tenfold (for example) greater
affinity for process A over process B, then it can be
said to have selectivity for process A.
However, the implication is that the different activity
is not absolute, that is, given enough molecule, the
activation of the other process(es) will occur.
Specificity :
This can be thought of as an extreme form of
selectivity where, in this case, no increase in the
concentration of the molecule will be sufficient to
activate the other process(es).

15. Full agonist :
Name given to an agonist that produces the full
system maximal response (Emax).
It is a system dependent phenomenon and should not
necessarily be associated with a particular agonist, as
an agonist can be a full agonist in some systems and a
partial agonist in others.
Partial agonist :
A partial agonist produces a maximal response that is
below that of the system maximum (and that of a full
agonist).
As well as producing a sub maximal response, partial
agonists produce antagonism of more efficacious full
agonists.

16. PARTIAL AGONISTS – EFFICACY
Even though drugs may occupy the same of receptors, the magnitude of their
effects may differ.
Full Agonist
1.0
Partial agonist
0.8
% Maximal Effect
0.6 Partial agonist
0.4
0.2
0.0
0.01 0.10 1.00 10.00 100.00 1000.00
[D] (concentration units)

17. Intrinsic activity :
The fractional maximal response to an agonist
relative to a standard “full agonist” in the same
system (where a full agonist produces the full
system maximal response).
Thus, a partial agonist that produces a maximal
response 50% that of a full agonist has an intrinsic
activity (denoted α) of 0.5. Full agonists have α = 1
and antagonists α = 0.

18. Absolute agonist potency :
Is the product of receptor stimulus (brought about
by agonist affinity and efficacy) and the
processing of the stimulus by the cell into an
observable response.
Because this latter process is system (cell type)
dependent, absolute potencies are system-
dependent measures of agonist activity.
Relative agonist potency :
Are system-independent estimates of agonist
activity that can be compared across systems
(provided both are full agonists).

19. Measuring Drug Action
 Efficacy and Potency
More
potent
than D2
D1 D2
100
% Response D3
Less
efficacious
than D2
0
Log [Drug]
…… Potency corresponds to the strength of a drug, while Efficacy corresponds to the
effectiveness of a drug.
…… e.g., if 5 mg of drug A relieves pain as effectively as 10 mg of drug B, drug A
is twice as potent as drug B
…… the diuretic furosemide eliminates much more salt and water through urine than
does the diuretic chlorothiazide. Thus, furosemide has greater efficacy than
chlorothiazide.
MEDC 603 Fall 2007

20. Measuring Drug Action
 Efficacy / Potency / Toxicity
Desired Response (%)
100 100
Toxicity (%)
50 50
0 0
Log [Drug]
Blue lines …. Drug 1
Red lines …. Drug 2
Solid lines …. Desired response
Dotted lines …. Toxicity response
MEDC 603 Fall 2007

21. More potent
Less efficacious

22. ANTAGONISM

23. Hemi-equilibria :
A pseudoequilibrium that can occur when a fast-acting
agonist equilibrates with a receptor system where a slow-
acting antagonist is present.
Under these condition, a slow-acting competitive
antagonist may appear to be an irreversibly acting
antagonist.
Insurmountable antagonism :
A receptor blockade that results in depression of the
maximal response.
Inverse agonist :
These ligands reverse constitutive receptor activity.
Currently it is thought that this occurs because inverse
agonists have a selectively higher affinity for the inactive
versus the active conformation of the receptor.

24. Pseudoirreversible antagonism :
True irreversible antagonism involves a covalent
chemical bond between the antagonist and the
receptor (such that the rate of offset of the
antagonist from the receptor is zero).
However, on the time scale of pharmacological
experiments, the rate of offset of an antagonist can
be so slow as to be essentially irreversible.
Therefore, although no covalent bond is involved,
the antagonist is for all intents and purposes
bound irreversibly to the receptor.

26. Noncompetitive antagonism :
If an antagonist binds to the receptor and precludes
agonist activation of that receptor by its occupancy, then
no amount of agonist present in the receptor compartment
can overcome this antagonism and it is termed
noncompetitive.
This can occur either by binding to the same binding
domain as the agonist or another (allosteric) domain.
Uncompetitive antagonism :
Form of inhibition (originally defined for enzyme kinetics)
in which both the maximal asymptotic value of the
response and the equilibrium dissociation constant of the
activator (i.e., agonist) are reduced by the antagonist.
This differs from noncompetitive antagonism where the
affinity of the receptor for the activating drug is not
altered.
Uncompetitive effects can occur due to allosteric
modulation of receptor activity by an allosteric modulator.

27. pAx :
Negative logarithm of the molar concentration of an antagonist
produces a x fold shift to the right of an agonist dose-response
curve (twofold for pA2).
pKB :
Negative logarithm of the KB. This is the common currency of
antagonist pharmacology, as pKB values are log normally
distributed and thus are used to characterize receptors and
antagonist potency.
pKI :
Negative logarithm of the KI, the equilibrium dissociation
constant of an antagonist-receptor complex measured in a
biochemical binding or enzyme study.
pD2 :
Historical term for the negative logarithm of the EC50 for an
agonist in a functional assay, not often used in present-day
pharmacology.

28. Types of Receptor Antagonists
Competitive Noncompetitive

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