Opiates 6 receptors

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.