Welcome to our unit on channel blockers.

It consists of two mini lectures.

We'll talk about mostly pore blocking
channel
blockers at ligand-gated channels in this
mini lecture.
And then in the next we'll talk about
blockers at voltage-gated channels.
These are general concepts and we will
flesh them
out when we talk about specific drugs for
specific
classes of diseases.
The general concept is a fairly simple
one.
It's that an ion channel opens and
conducts ions.
And then a blocker can come and sit more
or less within the
conducting pathway, blocking conduction
and interrupting the flow.
The blocker can then leave the channel and
the channel conducts again, and another
blocker ion of the same species, but
another blocker molecule, can come again
and sit in the channel and so on.
Now, this is a highly stylized view that
was developed before
single-channel recording and to some
extent before x-ray crystallography.
But here is a recording, one of the first
recordings of single channels from a
nicotinic
receptor in the presence of a channel
blocker.
So here is the unblocked channel in a
muscle nicotinic receptor.
And here is the recording in the presence
of a lidocaine derivitive, at about 20
micro molar.
And it does conform with more noise to the
idea that the channel
opens, stays open for a while, a blocker
comes in blocks conduction, the
channel the blocker dissociates, the
channel conducts
again, and so on, throughout the
recording.
So, this is a nice electrode physiological
correlation Of this simple idea.
And here is a structural correlate that is
relatively recent.
This was in fact the
first structural resolution, to my
knowledge, of a locker in an ion channel.
It is a bacterial pentameric ligand-gated
channel, which looks very
much like a, an animal ligand-gated
channel of the nicotinic receptor class.
And you'll recognize the mostly beta

strands in the extra-cellular

region, the mostly alpha helices in the
thin trans-membrane region.
So here it is seen from the side and the
blocker molecule is to scale for the rest
of the molecule.
Here it is from the top with the blocker
molecule, in the channel.
Now the blocker molecule is in fact a
lidocaine derivative
that has a bromine atom in it to be better
resolved
in x-ray crystallography.
And it sits more or less
where one would have expected, in the
middle of the conduction pathway.
So this is a very nice demonstration that
in fact structure and function
do more or less, confirm the schematic
notion.
Now, the question arises, are there there
are any useful blockers
for pentameric ligand-gated channel?
There are a few.
They are not in enormous clinical use.
One of them is mecamylamine which is
clinically used on
some occasions as a channel blocker of
peripheral nicotinic receptors.
The primary indication here is
hypertension because
peripheral nicotinic receptors strongly
control blood pressure.
A few years ago, mecamylamine, actually
one of its resolved enantiomers was
tested as a central nervous system drug
for treatment resistant depression.
But Mecamylamine failed in that trial.
Moving on to glutamate receptors, in
particular for
AMPA receptors, the antagonists, both
competitive and non competitive,
that is, both for the binding site, and
in the pore, have been generally useful
for research.
To figure out which receptors are involved
in a process and
to be able to, study a process
independently of AMPA receptors.
However, among the non-competitive
antagonists, one of
them, perampanel, was recently approved
for epilepsy.
So this is an exciting step forward for
the AMPA receptor field.
And you'll note that several of these
molecules have AMPA in their names.
We will talk about epilepsy in our unit on
epilepsy in greater detail.
Turning to the other major class of

glutamate receptor, the NMDA receptors.

Of course, we've talked about NMDA
receptors in the context of memory and
learning, and other neuroscience courses
talk about these concepts in great detail.
For the moment, we are speaking about
memantine, an NMDA channel
blocker that has been approved for
Alzheimer's disease.
So this would be the first drug for
Alzheimer's disease that is not a
cholinesterase inhibitor.
Memantine has this curious caged
structure, it's an adamantane derivative.
And it probably blocks primarily NMDA
receptors that are
not at the synapse but elsewhere on the
neuron,
for instance at the soma, and we call
these extrasynaptic NMDA receptors.
Probably, memantine binds at or near the
same site where magnesium binds.
In the famous story in which magnesium
binding renders
the NMDA receptor a coincidence detector
for memory and learning.
Here, however,
memantine is blocking the flux through
NMDA receptors, probably preventing
excitotoxicity and preventing neurons from
dying further in Alzheimer's disease.
Memantine binds near a site where another
famous research drug, MK801
binds, and where drugs of abuse, such as
PCP and Ketamine also bind.
So next time, we will talk about blockers
of voltage-gated channels.