The Opioid Analgesics

Stephanus Satria Wira Waskitha, M.Sc.

 The History of Opium
What do you think about analgesics in general?
Analgesics are medications that relieve pain. They work either by reducing inflammation or by changing the
way the brain processes and perceives pain.
Opiates - narcotic analgesics that are structurally related to morphine
Opioids - all the synthetic, semi-synthetic, naturally occurring, and endogenous compounds that interact
with opioid receptors in the body

The first opioids were extracted from opium — the sticky exudate obtained
from the opium poppy (Papaver somniferum )
 The active principle: Morphine
Opium contains a complex mixture of over 20 alkaloids. The one responsible for opium's analgesic
and sedative activity is morphine

Because morphine was poorly absorbed orally, it was little used in medicine until the hypodermic
syringe was invented in 1853
Injecting the drug directly into the blood supply revealed that morphine was a potent analgesic and sedative,
and was far more effective than opium

acting mainly in
the brain
As a potent Elevating the pain threshold thereby
painkillers decreasing the brain’s awareness of pain.

Side Effects?
There are large number of side effects such as depression of the respiratory center,
constipation, excitation, euphoria, nausea, vomiting, itching, pupil constriction,
tolerance, and dependence
 Structure and Properties of Morphine
Morphine was an extremely complex molecule by nineteenth-century standards, and identifying its
structure posed a huge challenge to chemists

By 1881, the functional groups on morphine had been identified, but

Why?
it took many more years to establish the full structure

History of morphine discovery:

Morphine isolation Full structure discovery X-ray crystallography structure

1804 1925 1968

Functional groups:
An amine, phenol, alcohol, aromatic ring, ether bridge, and alkene double bond.
 Structure-Activity Relationship
Here are morphine-like compounds:

The hydroxyl group

Retained
(6) is not crucial to
analgesic activity
analgesic activity

However, these compounds act differently:

Drop of analgesic The importance of

activity phenolic group
 Structure-Activity Relationship
Concluding of the study, it exhibited that:
The important functional groups for analgesic activity are the phenol OH group, the aromatic ring, and the
tertiary amine which is protonated and ionized when the drug interacts with its target binding site
Showing the pharmacophores:

If look carefully at the

morphine structure

It was noticeable that the activity of synthetic morphine was half

that of natural morphine!

This should come as no surprise as the macromolecules targeted by drugs are themselves
asymmetric and are able to distinguish between the enantiomers of a chiral drug.
 Structure-Activity Relationship
Epimerization of a single asymmetric center is not beneficial for activity either, as changing the
stereochemistry of even one asymmetric center can result in a drastic change of shape that could
affect how the molecule binds to its target binding site.
How does it mean?

Showing the importance and relation

between configuration and conformation

What is the other aspect explaining activity?

The pharmacophoric triangles - the corners
correspond to functional groups or binding
interactions
 The Opioid Receptors
It is now known that morphine activates analgesic receptors in the central nervous system (CNS)
and that this leads to a reduction in the transmission of pain signals to the brain
What are the receptors?
There are three main types of analgesic or opioid They are G-protein-coupled
receptor that are activated by morphine: receptors
the mu (µ), kappa (κ), and delta (δ) receptors
A newer form of terminology has now been introduced i.e., called the MOR, KOR, and DOR receptors
respectively
A fourth opioid receptor was later identified in the 1990s which shows a lot of structural similarity to the
classical opioid receptors i.e., opioid receptor-like receptor (ORL1) or NOR (nociceptin receptor) receptor.

ORL1 receptor Either increase or decrease the sensitivity to pain depending on the location of
activation the receptor and the method by which agonists are administered

Activation – Effects
µ receptor activation
δ receptor activation
κ receptor activation
The Opioid Receptors
Sedation and the strongest Side effects
Respiratory depression,
analgesic effect euphoria, and addiction.
Side effects
Analgesic No euphoria, no addiction, no sedation
effect Side effects
No effect on breathing, no euphoric effect, low
risk of physical dependence

So, will we design morphine-like compound to activate κ receptor selectively?

Further studies showed that activation of κ receptor can lead to sedation and psychological side effects
as anxiety, depression, and psychosis.

Morphine, and most of its analogues, bind In consequence

Powerful analgesic activity and
strongly to the µ receptor but less strongly to most serious side effects
the κ and δ receptors.
Morphine: Pharmacodynamics and Pharmacokinetics
Pharmacodynamics refers to the manner in which a drug binds to its target and produces a
pharmacological effect

The functional groups that are important to the activity

of morphine act as binding groups:
1. The phenolic group
2. The amine group (protonated)
3. The aromatic ring

Remember that the active

conformation of morphine is also
important
Morphine: Pharmacodynamics and Pharmacokinetics
Pharmacokinetics refers to the ability of a drug to reach its target and to survive in the body.
Morphine is relatively polar and is poorly absorbed from the gut, and so it is normally given by
intravenous injection
In fact,
Only a small percentage of the dose administered actually reaches the
analgesic receptors in the CNS because of the blood–brain barrier
(remember and why?)
How about normorphine compared to morphine regarding its analgesic
Morphine contains a nitrogen
activity? atom as the weak base

The secondary NH group is more polar than the original tertiary group, and so
normorphine is less efficient at crossing the blood–brain barrier, leading to a drop in
activity.

Can you explain about polarity and basicity of nitrogen

in morphine or morphine-like compounds?
 Morphine Analogues
Considering the problems associated with morphine there is a need for novel analgesic agents which
retain the analgesic activity of morphine, but which have fewer side effects and can be administered
orally. The efforts were substituents variation and drug extension

a) Substituents variation
A series of alkyl substituents were placed on the phenolic group, but the resulting compounds were inactive
or poorly active. We have already identified that the phenol group must be free for good analgesic activity

Therefore, another strategy was selected

 Morphine Analogues
b) Drug extension
The strategy of drug extension involves the addition of extra functional groups to a lead compound in
order to probe for extra binding regions in a binding site.

The introduction of a hydroxyl group at position 14 increases activity for structures such as
oxymorphone and oxycodone
suggesting

There might be an extra hydrogen bond interaction

taking place with the binding site.
 Morphine Analogues
b) Drug extension (cont’d)
So let’s take a look at these analogues:

However, when the phenethyl group was attached:

How could this happen?

showing

A strong indication that a hydrophobic binding region has been

located which interacts favorably with the new aromatic ring
 Morphine Analogues
b) Drug extension (cont’d)
So let’s take a look at other analogues:

How could this happen?

Naloxone Naltrexone Nalorphine

(no analgesic activity) (no analgesic activity) (weak analgesic activity)

They act as antagonists to morphine

Antagonist to morphine or opioid receptors antagonist - they bind to the analgesic receptors without
‘switching them on’ and then block morphine from binding

So, what are the main clinical uses of opioid receptor antagonists?
 Morphine Analogues
b) Drug extension (cont’d)
For many years, chemists had been trying to find a morphine analogue without serious side effects.
There had been so little success in this search that many believed it would be impossible to separate
the analgesic effects from the side effects.
However, a glimmer of hope appeared until they found:

It acts as an antagonist at the µ receptor and as a weak agonist at the κ receptor

Therefore

The slight analgesia observed with nalorphine is due to

partial activation of the κ receptor
Nalorphine
(weak analgesic activity)

Unfortunately, nalorphine has hallucinogenic and psychological side effects, which result
from activation of the κ receptor
 Morphine Analogues
c) Simplification or drug dissection
The main purpose of this effort was that if the molecule could be simplified, it would be easier to synthesize
analogues
Considering morphine structure:

removing the ring Easier to synthesize it But how

and scale up the target is the activity?
compound

1. Removing ring E
Removing ring E leads to complete loss of activity. This emphasizes the importance of the basic nitrogen to
analgesic activity.
 Morphine Analogues
2. Removing ring D
Removing the oxygen bridge, as well as the alcohol and alkene functional groups gives a series of
tetracyclic compounds called the morphinans which have useful analgesic activity.

Important notes:
1. Some morphinans are more potent and longer-acting than their morphine counterparts, but they
also have higher toxicity and comparable dependence characteristics
2. SAR studies implies that morphine and morphinans are binding to the same receptors in the same
way
3. The morphinans are easier to synthesize as they are simpler molecules with fewer rings and chiral
centers
 Morphine Analogues
3. Removing ring C and D
Removing both rings C and D gives an interesting group of compounds called the benzomorphans which
retain analgesic activity. One of the simplest of these structures is metazocine, which has the same
analgesic activity as morphine.
Examples:

The interesting discovery was that:

Pentazocine has been proved to be a useful long-term analgesic with a very low risk of addiction.
Pentazocine acts as an antagonist at the µ receptor but it is a full agonist at the κ receptor rather than a
partial agonist. Pentazocine also acts as a weak agonist at the δ receptor.

So, what are the conclusions?

 Morphine Analogues
4. Removing ring B, C, and D
Removing rings B, C, and D gives a series of compounds known as 4-phenylpiperidines

Furthermore, the activity can be

giving
increased sixfold by introducing the
phenolic group and altering the
ester to a ketone

ketobemidone
Weaker analgesic activity and shorter
duration of action
Further developments:
When a cinnamic acid residue was attached to
pethidine, it resulted in highly increasing
analgesic activity. But no activity when
attached to morphine!

Why would this happen?

 Morphine Analogues
4. Removing ring B, C, and D (cont’d)
Fentanyl and its analogues represent a class of opioids known as the 4-anilinopiperidines and are among
the most potent agonists known for the µ receptor

Based on fentanyl structure,

How can this compound have 100
times higher analgesic activity
compared to morphine?

The easiness of the compound

through in blood-brain barrier

They act as analgesic agent with short duration of action (why)

 Morphine Analogues
4. Removing ring B, C, and D (cont’d)
So, the conclusions are:
1. The rings C, D, and E are not essential for analgesic activity.
2. Piperidines retain side effects, such as addiction and depression of the respiratory center,
because they are agonists at the µ receptor.
3. Piperidine analgesics are faster acting and have a shorter duration of action than morphine.
4. The aromatic ring and basic nitrogen are essential to activity, but the phenol group is not.
5. Piperidine analgesics appear to bind with analgesic receptors in a different manner to previous
structural classes.
 Morphine Analogues
5. Removing ring B, C, D, and E
The analgesic methadone was discovered in Germany during World War II and is comparable in activity
to morphine. It is orally active and has less severe emetic and constipation effects.

The difference in activity is most probably

due to receptor–ligand interactions

methadone chemical structure

Other compounds:

Many analogues of methadone have been synthesized, such as

dipipanone, which is an oral analgesic, and l-α-acetylmethadol (LAAM)
 Morphine Analogues
Rigidification
The aim is to retain the active conformation for the desired target and eliminate alternative conformations
that might fit different targets.
hopefully should Increase activity, improve selectivity, and
Rigidification decrease side effects.
of compound

Comparison of morphine and orvinols 10.000 more potent than morphine More than 10-fold more potent than
(oripavines) chemical structure (why?) etorphine
(one of the most potent analgesic ever
reported)
The existence of a lipophilic group at C20 is found to improve activity drastically
 Antagonists and Agonists
In the previous discussion, we might be curious about why should a molecule such as nalorphine act
as an agonist at one analgesic receptor and an antagonist at another?
Let us assume that an opioid receptor exists in an active or an inactive conformation
The active conformation is capable of binding G-proteins and triggering signal transduction, while the
inactive conformation is not
The binding sites of the active and inactive forms of There are many Related to
the receptor are capable of distinguishing between conformations of induced-fit theory
the structures of an agonist and an antagonist binding site
Illustration:
 Antagonists and Agonists
Let us now consider the binding of the agonist N-phenethylmorphine. Like morphine, it binds using
its phenol, aromatic, and amine functional groups. The aromatic ring of the phenethyl group is quite
far from the amine group.

Hence, it overlaps more effectively with the more distant hydrophobic region
causing the equilibrium to shift to the active form of the receptor
 Antagonists and Agonists
Now consider what happens if the phenethyl group is replaced by an allyl group.
The allyl group is much closer to the amine and interacts better with a closer hydrophobic region.
Therefore, the equilibrium would shift to the inactive conformation

So, how do we explain the fact that some opioids act as an agonist with
one type of opioid receptor, and as an antagonist at another?

The relative positions of the extra hydrophobic regions

are different in the different types of receptor
 Antagonists and Agonists

1. A plus sign indicates that the compound acts as an agonist, whereas a minus sign means that it acts as an antagonist
2. The number of plus signs or minus signs indicates the binding affinity
3. Plus signs in brackets indicate partial agonist activity.

The search for κ-selective agents has resulted in the clinically useful agents nalbuphine and butorphanol

Nalbuphine has the same activity as morphine, low addiction liability, no

psychotomimetic activity, but is orally inactive.
Butorphanol is also orally inactive

Could you guess the resulted side effects?

 Endogenous opioid peptides
Morphine relieves pain by binding to analgesic receptors in the CNS, which implies that there must be
endogenous chemicals which interact with these receptors
The search for these natural analgesics took many years, but led, ultimately, to the discovery of the
enkephalins
They are produced mainly in the central nervous
system, adrenal medulla, and other peripheral
tissues
A polypeptide-based opioids
(slight preference for the δ receptor)

More examples: Enkephalins, dynorphins,

and the endorphins

All of these compounds have either the Met- or

the Leu-enkephalin skeleton at their N–terminus
The endomorphins have a strong (explaining the analgesic activity)
affinity and selectivity for the μ receptor.
 Endogenous opioid peptides
One suggestion is that the remaining peptide chain of each molecule is responsible for targeting
each peptide to particular types of analgesic receptor.
It is known that enkephalins show preference for the δ receptor, whereas dynorphins show selectivity for
the κ receptor, and ß-endorphins show selectivity to both the µ and d receptors. Hence, this led to
message-address-concept
Message-address concept – part of a molecule is responsible for its pharmacological activity (the message)
and another part is responsible for its target selectivity (the address)
 Endogenous opioid peptides
How about molecule targeting ORL1-receptor?
The most recent endogenous opioid ligand was discovered in 1995 by two groups and was named
nociceptin or orphanin-FQ, which was derived from protein pronociceptin/orphanin FQ
Curiously, the N-terminal amino acid is phenylalanine rather than tyrosine and it appears that this plays a
crucial role in receptor selectivity.
The endogenous opioids, such as the enkephalins, endorphins, and dynorphins, have tyrosine at the N -
terminus and have no affinity for the ORL1 receptor, whereas nociceptin/orphanin-FQ has negligible affinity
for the μ, κ, and δ receptors.
Chemical structure of nociception:

Simplification
 Endogenous opioid peptides
Enkephalins analogues and selective δ- selective opioids
SAR studies on the enkephalins have shown the importance of the phenol ring and amino group of the
tyrosine residue. Without either, activity is lost. If tyrosine is replaced by another amino acid, activity is also
lost
Problem faced:
It has been found that the enkephalins breaking the bond (peptide link)
are inactivated by peptidase enzymes between tyrosine and glycine
in vivo
Several strategies:

Study case:
Is that possible to replace L-alanine with D-alanine and L-tyrosine with D-tyrosine to
overcome this problem?
 Endogenous opioid peptides
Binding theories of enkephalins
Based on SAR studies on enkephalins, it revealed the tyrosine residue and the aromatic ring of
phenylalanine are important for analgesic activity, which suggests that they act as important binding
groups in their interaction with opioid receptors
The proposed interactions showed below:
Explanation:
1. There are two hydrophobic binding
regions (T-binding and P-binding
region)
2. Two hydrophobic binding regions
may be approximately equidistant
from the ionic binding region
 Endogenous opioid peptides
Binding theories of enkephalins
More examples of the binding mode between morphine and pethidine: