Antagonists and modulators

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

no efficacy; i.e. it does not produce a functional effect after it
binds. Antagonists can 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.

Types of antagonists
1. Competitive
2. Irreversible
3. Non-competitive
Competitive antagonists shift agonist concentration-
response curves to the right but do not affect the maximal
possible response.
Irreversible antagonists compete for the same site as agonists and
either bind them so tightly (or covalently) that those sites are no longer
available for agonists to bind. They decrease the maximal possible
response to agonists.

Irreversible Antagonism
No change in
agonist EC50
I

3xI

10 x I
Non-competitive antagonists bind to a site on the receptor distinct from
that of the agonist.

Non-competitive

No change in
Non-competitive agonist EC50
antagonists decrease
the maximal response
without affecting the
agonist EC50 (eg.
channel blockers).
 Allosteric modulators bind to a site on the receptor distinct from that of
the agonist and affect receptor function. They have no effects in the
absence of agonist.
Non-competitive
They may have several
different effects. No change in
agonist EC50
1. Decrease the agonist
EC50 without affecting
agonist maximal
response (eg.
benzodiazepine site
agonists)
2. Increase the agonist
EC50 without affecting
agonist maximal
response (eg.
benzodiazepine site
inverse agonists)
 Receptor diseases

Abnormalities can exist in the densities of receptors (Bmax)

or in their dissociation constants (Kd).

In Parkinson’s disease a higher than normal density of

dopamine receptors is found in the putamen and caudate
nucleus following degeneration of dopamine-releasing
neurons in the substantia nigra (that sends neuronal
projections to the caudate/putamen).
Startle diseases such as hyperekplexia are due to a
decreased potency of glycine at the glycine receptor. This
is caused by several different single amino acid mutations
in the glycine receptor (but this mutation is not near the
glycine binding site).
 Receptor diseases continued...

In some diseases such as insulin-resistant diabetes, the

tissues are unresponsive to drug. This phenomenon is
synonymous with drug tolerance or drug desensitization.
This can be due to to there being fewer drug receptors on
the cell membrane with which drug can interact (as in the
case of insulin-resistant diabetes).

There are also autoimmune diseases of receptors. A

classic example is myasthenia gravis where circulating
antibodies against acetylcholine receptors decrease the
numbers of receptors at the neuromuscular junction.
Possible changes in
receptors that may
account for altered
tissue sensitivity to
a drug.
 Spare receptors

Not all receptors need be occupied in

order to give a maximum effect of a drug;
spare receptors exist to give a biological
safety margin.
In the neuromuscular junction there are
about 20,000 acetylcholine receptors, of
which 1/4 to 1/2 can be blocked without
affecting the maximal muscle twitch
response.
Gap junctions between cells (electrically linking
them) mean that stimulation of receptors on one
cell can lead to effects in as many as 200 cells
How do drug effects get transduced from outside
to inside the cell?