In this section of our opiates unit,
we will look at the different receptors
that opiates bind to
and examine some
analgesic receptor theories.
This is a reminder that this presentation
is Dr. Johnson’s intellectual property
and contains proprietary images
used with permission of
Oxford University Press.
The Beckett-Casy Hypothesis
is an early model for opiate receptors.
In this model,
there is only one opiate receptor.
A lock and key analogy
is used to suggest
that morphine fits into
a hydrophobic slot on the receptor.
This model is successful at predicting
the pKa of 7.8 to 8.9 for analgesics
and the requirements for the aromatic ring
with phenolic hydroxyl group
and the nitrogen atom.
However, the model also has
a number of failures.
It predicts a requirement for
an ethylene bridge
to bind in a hydrophobic slot.
This prediction does not
align with reality
because not all analgesics
have this structure.
For example, fentanyl lacks this bridge.
The model does not include
an extra binding site
discovered by drug extension,
it does not explain the antagonist effect
of the N-allyl and N-cyclopropyl groups,
and it does not explain why
a cinnamic acid extension
improves the analgesic
activity of pethidine
but eliminates the activity of morphine.
So, the model needs to be revised
to incorporate these findings.
One conclusion based on
these observations is that
there are multiple analgesic receptors.
The next model of analgesic receptors
is based on there being
multiple receptors.
All require the phenol, aromatic ring
and nitrogen atom.
However, subtle differences
between receptors creates preferences
for one analgesic vs another,
and different interactions
between receptors and their ligands.
To date there are four opiate receptors,
µ, κ, and δ, and a fourth
that has only recently been discovered.
The σ receptor was at one time
thought to be an opioid receptor,
but has since been found to have
no relationship to nociception,
our feeling of pain.
The receptors have been
cloned and sequenced
and their structures studied.
In addition, there have been
some agonists developed that are
selective for individual receptors.
Another theory of opiate receptors
is that some of them
can form receptor dimers
in certain tissues.
These could be homodimers;
that is, made up of two of
the same opioid receptor type,
or heterodimers, made of
two different opioid receptor types.
The idea behind these dimers
is that the transmembrane
regions can intertwine,
resulting in hybrid binding sites,
which are different from
the binding sites presented
by receptor monomers.
The implications of receptor dimers
include binding of an antagonist
at one hybrid site may affect
ligand binding at the other site.
This could explain the results
attributed to receptor subtypes.
If this is true, then agents selective for
hybrid sites could be designed.
MDAN-21 is a hybrid structure involving
the µ-selective agonist oxymorphone
linked to the δ-selective
antagonist naltrindole.
It is 50 times more potent than morphine
and shows no tolerance or dependence.
At this point we are left
with two key questions.
First, how can different receptors
distinguish between
small differences in ligands?
And secondly, why should changing
the N-methyl to N-allyl group
change a drug from an agonist
to an antagonist?
We can address these questions
if we consider that an opioid receptor
can exist in equilibrium
between two conformations.
The active conformation
is capable of signal transduction
via an inhibitory G-protein,
while the inactive conformation
sends no signal.
In this model, agonists and antagonists
can bind to the receptor.
Agonists stabilize
the active conformation,
increasing signal transduction,
while antagonists stabilize
the inactive conformation,
resulting in an overall
decrease in signal transduction.
Now for the receptor to distinguish
between agonists and antagonists,
the active and inactive conformations
must be different
binding conformations
The receptors have a binding site
for the main part
of the morphine structure,
and an additional hydrophobic binding area
that has a different size and distance
from the main binding site
depending on whether
the receptor is in an active
or inactive conformation.
Agonists have good overlap
with the additional
hydrophobic binding region
of the receptor in
its active conformation,
and poor overlap with this region
on the inactive conformation
of the receptor.
Therefore, agonists bind better
to the active conformation
of the receptor and stabilize it.
Antagonists on the other hand
have good overlap
with the hydrophobic binding area
of the inactive conformation
of the receptor
and poor overlap
with this part of
the active conformation.
Therefore, antagonists bind better
to the inactive conformation
of the receptor,
and stabilize this.
All four opiate receptors are
G-protein coupled receptors
and have 7 transmembrane helices
as an integral part of their structure.
The receptors bind to
inhibitory G-proteins.
Activation of the receptors
upon agonist binding
releases the G protein
which then inhibits
other cellular processes.
For example, agonist binding of
the µ receptor leads to:
closure of voltage sensitive
calcium channels,
stimulation of potassium efflux,
and inhibition of adenyl cyclase
which in turn results in
a decrease of cyclic AMP.
There is reason to believe
that the other opiate receptors
behave in a similar manner.
When we consider
the apparent functions
of the different opiate receptors,
an ideal analgesic would cause
analgesia and possibly sedation,
but not respiratory depression
or addiction.
It does not appear that it is possible
to target just one of the receptors
to get optimal effects;
each of them has advantages
and disadvantages.
In this unit, we looked at
the properties of opiate analgesics,
different classes of these
and the effects of
changing the structures.
Finally, we looked at
some receptor theories
to understand how minor changes in
ligand structure can have
dramatically different
effects on the receptor.