Receptor

theory: 1
Dr Laura Aitken
la49@st-andrews.ac.uk

What is receptor theory?

Text

This is the idea that drugs act by binding to

receptors
The consequences of these binding interactions is
that a physiological or pharmacological change
occurs
There is an excellent chapter on this in the Rang
and Dale textbook please read it!

What are drugs?

They interact with biological structures to produce pharmalogical effect.
So these structures can be anything from proteins, DNA, diff types of
transmembrane receptors & trigger some sort of signalling cascade
to have an effect

A drug is a chemical compound that is administered to

produce a desirable physiological or psychological effect.
Side effects are undesirable changes caused by the drug

What is a receptor?
Molecule to which drug can bind

In response to binding a physiological change must take place

D

Not all drugs interact with receptors but most do

Exceptions: antacids and osmotic diuretics
Antacids = go straight into stomach and neutralises acid (does not have
receptor)
Osmotic Diuretics = deals with changes in osmotic pressure

Schematic. R = receptor. D = drug.

- Many diff types of receptors.
- Key thing: when the interaction between drugs and receptors happen,
there will have some sort of response.

How does a drug bind to its receptor?

Weakly

Through:

van der Waals forces, H-bonds, ionic interactions

Reversibly
Think of enzyme-substrate binding

D + R [DR] EFFECT
to get an
a reversible reaction
to produce this complex [DR]

There are four main types of receptor

Ion channels
e.g. neurotransmitter drugs
G-protein coupled receptors
e.g. adrenergic agents
Enzymatic receptors
e.g. insulin
Intracellular receptors
e.g. steroid hormones

Ion channels
- Fastest effect
GPCR
- Most common.
Enzymatic
- Mostly steroid hormones
Intracellular
- Will talk more about these in detail

Drug Receptor Interactions

Ion channel
- Drug binds to receptor. Causes
changes to channel. Hyper/depolarisation occurs and causes a
cellular effect.

Enzymatic Receptor
- Coupling to enzyme to get phosphorylation/dephosphorylation to get
cellular effect

GCPR
- G protein produces secondary
messengers (CMP) to produce
all sorts of down stream effects
- Most common (e.g. Adrenaline)

Intracellular receptors
- Transcription involved. Drug comes
and needs to get through the cell
membrane. So needs to be hydrophillic.
- Once its through, it will be out of
cytoplasm and binds to receptor.
mRNA synthesis occurs.
- e.g. Steroid hormones (estrogen)

Properties of receptors
Recognition
Conformation of receptor must allow saturability,
reversibility, stereoselectivity, agonist specificity and tissue
specificity
Transduction = its going to produce a response
Different receptor types are linked to effector systems either
directly or through simple or more-complex intermediate
Saturability signal amplification systems
- when there is a lot of drug and a fixed number of
receptors, it will reach a point where it is saturated
and no more drugs can bind to the receptors
anymore. This is the maximum effect.

Agonist specificity
- An agonist (drug). Drugs if they look the same, theyre
probably gonna have similar effects and bind well. In reverse,
if they dont look similar, they wont have similar effect.

Reversibility
- Due to weak van der Waals forces etc. [Non
covalently]

Tissue Specificity
- Targeting a specific area of the body, you want it to get
somewhere (a membrane e.g.), binding should be endogenous
to that ligand only.

Stereoselectivity
- How the compound is made up. Which orientation
is it in? + or -? S or R? Must be in correct
conformation to bind.

How can we predict that a drug will elicit

a response in a particular tissue?
Can the drug get to the tissue? Can it get across?
much of it will be in the reversible reaction? Is there
Equilibrium of drug at receptor How
going to be enough it?
Response will depend on downstream signalling apparatus

Agonists and antagonists

Describe drug actions on receptors

An agonist is a drug that binds to a receptor eliciting a cellular
response
An antagonist prevents the actions of an agonist stops the binding
There is a silly video on youtube about this:
http://www.youtube.com/watch?v=hR4OUviDhSI

Agonist properties
Affinity
Intrinsic activity
Effect

D + R [DR] EFFECT
Affinity
- how much do you want to bind to the receptor.
Intrinsic Activity
- Elliciting a response.

Natural agonists
Most receptors have naturally occurring molecules that bind to
them
Search for synthetic analogues = rational drug design
e.g. CNS opiate receptors:
Natural agonist = endorphins
Synthetic agonist = morphine
Both cause same effects (pain reduction, euphoria)
e.g. endorphines. Produced when youre exercising.
It is a pain reduction. The next day after exercising and
you feel the pain, thats due to lack of endorphins.
That leads to a synthetic agonist
e.g. Morphine. Comes from natural products. Morphine
you get pain reduction but also euphoria.
= These two compounds produce the same effects. One
is natural, one is synthetic.

Receptor Theory
Biological responses to drugs are graded
These responses and their comparative size can be measured
There is a systematic relationship between the drug
concentration and the magnitude of the response obtained
= DOSE RESPONSE
The systematic way of doing this is by using a drug response
card. How does the concentration affect the response that we see?

A little bit of chemistryLaw of mass action

The rate of a chemical reaction is proportional to the product of the
concentration of the reactants
Law of Mass reaction

K2

[A] + [B] [AB]

K1

K1 =
K2 = dissociation

This can be applied to pharmacology

Key thing is the occupied receptors [DR].

K2

[D] + [R] [DR]

K1
[D] = drug concentration
[R] = receptor concentration
[DR] = concentration of occupied receptors
K1 = rate on
K2 = rate off

Why do we need this?

As we change the dose of a drug,

[D] will change

As this increases more receptors are occupied and so

increases
As this increases

[DR]

EFFECT increases too.

Understanding these equations allow us to describe how drugs and

their receptors interact

What else can this tell us?

AFFINITY of the drug for the receptor can also be

The
described

how well is the drug binding to the receptor?

The dissociation constant tells us the rate that drug receptor

when equilibrium is achieved, thats when we
complexes disassemble
can calculate how quickly it binds and how

Kd = K1/K2 = [D][R]/[DR]

quickly it doesnt bind. equilibrium = when

50% of receptors are occupied = when K1
and K2 are equal. That tells us the number of
associations and deassociations are the
same. **This is for every single drug!

The association constant tells us the rate that drug receptor

complexes assemble

Ka = 1/Kd = K2/1 = [DR]/[D][R]

This is important for excretion. How does it get out of the system? How is it affecting the body?
Association constant tells us how likely we are to get a drug receptor complex.

Occupancy theory

RESPONSE/ EFFECT the fraction of receptors that are

occupied

RESPONSE/ EFFECT = [DR]/[RT]

[DR] = number of occupied receptors
[RT] = total number of receptors.

All substances are poisons:

there is none which is not a
poison. The right dose
differentiates a poison and a
remedy
Paracelsus (1493-1541)

Dose response
A way of plotting out dose response cards to see the results and how
doses effect the response.

Dose-response curves can be used to plot the results of many

kinds of experiments.
The X-axis plots concentration of a drug or hormone.
The Y-axis plots response, which could be almost anything.
(e.g. enzyme activity, gene expression, membrane potential,
cell death)

Typical dose response elicited by an agonist

More drug = more effect
Maximal effect
Rectangular hyperbola

To get a handle on this type of data

Log dose response curves
Advantages:
The portion of the curve between 10% and 90% of the
maximum response is linear. This makes it easier to calculate
points from the graph.
4 parameters to deal with: base line, slope, EC50, maximal
response
= you then get a sigmoidal curve

Log dose response curves

More drug = more effect
Maximal effect
Sigmoid curve

EC50
Molar concentration of a drug used to produce half the
maximal response! Used to measure the potency.

4 parameters:

~ log -8.1

Baseline response
Maximum response ~150 arbitary units
half of that would be ~75
Slope
EC50

EC50 = effective agonist

concentration required to
give a 50% effect
EC50 = inverse log of -8.1

Potency: full agonists

Full agonist = its gonna occupy the receptor totally.
Most agonist will elicit a maximal response.
== The estimate of the absolute concentration of a drug which
is going to produce a response

Less potent full agonist

shifts dose response curve
to the RIGHT
More potent full agonist
shifts dose response curve
to LEFT
This less potent full agonist is probably a structurally
similar drug. But less potent as it takes a much larger
concentration to reach its maximal response.

Potency: partial agonist

Wont illicit a full response. Will produce a lower maximal
response compared to full agonist. Usually takes longer
and higher concentration to saturate it.

Partial
agonist

Partial agonist will shift the

maximum response DOWN

Cooperativity
If youve got positive cooperativity = drug will bind to receptor and it will
help another one = increases affinity. Negative = drug will bind to receptor and a second molecule
might not be able to bind as well = decreases affinity for next molecule.

Positive cooperativity will

STEEPEN the slope of the
dose response curve for an
agonist
Negative cooperativity will
FLATTEN the slope of the
dose response curve for an
agonist
Probably does not reach the maximal response,
but able to reach there eventually = much flatter
slope.