Now, this apparent contradiction that quaternary
ammonium salts were shown to both contract
and relax smooth muscle galvanised the idea
of a receptor.
A receptor, in physiological terms, is a site
where a drug binds. And then the receptor
brings about a physical response.
In the context of what we were discussing,
which is contraction and relaxation, let us
consider the cholinergic system. So, this
is the idea that we have a receptor which
responds by relaxing muscle in its normal
state. Let’s have a look at this in terms
of our cartoon.
We have here our drug, which is shown as the
yellow circle, and we have our receptor, which
is shown here as the green rather hungry pac-man.
What’s happening in this scenario is that
you have a drug receptor complex. You have
selective binding of the drug for the receptor
and then this yields an appropriate response.
This is the idea of receptors and drugs interacting
with each other. And it’s pretty basic and
straightforward, but it governs a lot of what
we observe in terms of the responses we see
when we are applying drugs to a given tissue
The drug is a ligand at this receptor and
that’s an important term to remember. This
is something which is a ligand or ligates
at the particular receptor. It is something
that binds to it. It is described, in this
case, when it results in the production of
a response as an agonist. In this case, a
muscle relaxant, the receptor was identified
by being in the family called the cholinergic
receptors, which I mentioned earlier. And
a naturally-occurring agonist at this class
of receptor is acetylcholine. Hence, the name
cholinergic. And indeed, when this was first
discovered, it was actually christened by
its German name, Vagusstoff.
The drug was found to contract... were found
to contract the muscle were shown to be acting
at actually the same receptor. But, of course,
they were doing something quite different.
They were found to be binding to the receptor,
but without giving rise to the physical response
that was associated with the binding of acetylcholine.
And it was hypothesised that what was actually
happening, in this case, is that the drug,
in here for the sake of clarity represented
as the red square, was binding to the receptor
and forming a drug-receptor complex. But,
this was not yielding a response. The question
had to be asked: why? If it’s binding, surely
the process of binding results in that response.
So, the concept of the antagonist was born
because the idea was that, because the receptor
was actually blocked, acetylcholine itself
could not bind and therefore, by not being
able to bind, couldn’t actually elicit the
appropriate messenger response. Since acetylcholine
couldn’t act there, the muscle went into
a state of contraction mostly because there
are other receptors that actually deal with
the sympathetic contraction force. And the
cholinergic system is largely concerned with
the parasympathetic relaxant force.
Drugs which block active sites without giving
rise to a response are called antagonists.
Other active sites where drug combined include
enzymes. And as we’ll see, an enzyme is
something which actually involves the conversion
of a molecule into more than one molecule
or, sometimes, the bringing together of two
molecules to form a third.
Both receptors and enzymes are made up of
proteins. And that’s why I said earlier
on in Module III why proteins and polypeptides
were so important, as is their understanding.
Proteins contain a variety of functional groups.
So, we have to ignore, for the sake of argument,
that it is effectively just a polyamide backbone.
Yes, of course, the polyamide or polypeptide
primary structure is important. But, it’s
the side chains that we saw on the other amino-acids
back in Module III which convey on it different
types of potential intermolecular interaction.
We have things like glutamic acid which, of
course, as the name suggests, has an acidic
extension part coming off the alpha carbon.
We have neutral species, neutral species,
for example, like isoleucine, which is purely
aliphatic. We also have basic species like
arginine and lysine which, on their side chain,
have NH2 and also amidine and guanidinium
groups. In addition, we also have the polar,
which, for example, could be something like
serine, which contains an alcohol group, and
non-polar like, for example, valine. So, there’s
a whole host of different groups on the side
chains which have... can influence the interaction
between a drug and a receptor.
Drugs will form interactions with the functional
groups lining the active site. And this is
important because in the receptors that we
will discuss, there is a bulk of protein and
then there is the key active site which contains
certain key amino-acids whose interaction
through intermolecular forces with our agonist
or indeed, with our antagonist, are so crucial
for that biological activity.
Drugs are recognised by their targets by a
number of different types of interaction.
And we’re going to be going through some
of these now.
Drug binding at the same site, but in a different
way can give rise to different effects. And
this is the difference between agonists and
antagonists. You could also get something
called a partial agonist. But, we will probably
leave that alone for the moment.
Knowledge of these interactions allows us
to change the structure of the drug in order
to afford a better interaction. It helps us
to work out how a drug binds and it also helps
us to design new drugs and predict how they
will bind in an ideal world.