Opioid Analgesics
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Terms and Definition • Opiates are narcotic analgesics that are related to morphine in
structure.
• Opioids are molecules either synthetic, semisynthetic, naturally occurring or endogenous that can interact with opioid receptors in the body and alleviate the pain
• Orphan receptor is a novel receptor in which ligand binding to it still not known.
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History of opium and morphine
• The first opioid compound was extracted from opium. It is obtained from the sticky exudate from opium poppy (Papver somniferum).
• It is used as sedative and for treatment of diarrhoea.
• It was used by Royal British Navy as sedative during sailing.
• Famous nineteenth-century authors and poets have taken opium in regular basis and were addicted to it.
• Some communities started to smoke it especially in China.
• Due to problems associated with it, it was restricted in the twentieth century for medical and scientific purposes.
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www. google.com/images 3
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• Opium contain more than 20 alkaloids,
however the active alkaloid in it is
morphine.
• Morphine extracted in 1803 and then
isolated and purified in commercial scale
in 1833 by chemists from Macfarlane-
Smith firm in Edinburgh.
• It used in medicine when the syringe
was invented in 1853.
• Morphine revealed that it is a potent
analgesic and sedative.
• Risks were associated with it are
addiction, tolerance and respiratory
depression.
Structure and Properties of Morphine • At the time of the isolation of morphine, it was a challenge
to identify the structure. Usually chemists used to degrade compounds into smaller compounds that are already known.
• In 1925, Sir Robert Robinson proposed a structure for morphine. The synthesis of this structure was done in 1952 and it is proven by X-ray crystallography in 1968.
• Morphine contains five rings labelled A-E and has T-shaped structure.
• It contain tertiary amino group, phenol, alcohol, aromatic ring, ether bridge and alkene double bond.
• It is consider basic compound because of the tertiary amino group
• The nitrogen atom can undergo inversion as it can convert between the axial and equatorial positions.
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Opioid Receptors
• Opioid receptors are available in the CNS that lead to reduction in the pain signals to the brain.
• There are three main receptors for opioids, mu(µ), kappa (ĸ) and delta (δ). Also, there are new names for these receptors, MOR, KOR and DOR receptors.
• A fourth type of receptors also now has been discovered called (opioid receptor-like receptor) (ORLI). It is now known as NOR. It is a type of orphan receptors as the endogenous ligand that bind to it not known.
• Recently it have been known as that opioid receptors can occur as homomeric and heteromeric.
• Opioid receptors are G-protein-coupled receptors which activate Gi or Go signals.
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Mu receptors
• Potent analgesia
•Dangerous side effects as respiratory depression, euphoria, addiction and physical dependence
Kappa receptors
• Less analgesia
• Side effects such as anxiety, depression and psychosis
Delta receptors
• Less analgesia
•Does not cause sedation, euphoria, or physical dependence
Activation of opioid receptors by morphine has different effects
SAR of Morphine
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• Important groups for analgesic groups of morphine are
phenol OH group
Aromatic ring
Tertiary amine
Relative position of functional groups
Contain five asymmetric centers at C5, C6, C9, C13 and C14. However the natural morphine is available as single stereoisomer.
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• Changing the stereochemistry of one
asymmetric center result in decrease
in activity.
• There are doubt about the
importance of OH group when the
drug come to in vivo as the
pharmacokinetics affect the activity
• The OH group can undergo
metabolic conjugation when it reach
to the body easily which will affect
their bioavailability to CNS rather
their important binding interactions
that can do it.
• Masking of OH group or missing it
will lead to increase their
hydrophobicity and so molecules
can cross BBB easily.
Pharmacokinetics of morphine
• Morphine is injected as intravenous injection because it is relatively polar in order to prevent its metabolism.
• The amine group is consider as weak base, so it can exit as a free base and ionized from. The free base can cross BBB and then protonated to interact with the receptor.
• The pKa is 7.8 – 8.9 for useful analgesics.
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Oxymorphone
• Modification of hydroxyl group at position 6 increases the activity
• Introduction of a hydroxyl group at position 14 increases the activity than morphine
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Morphine analogues
Heroin
• Acetylation of the phenol and hydroxy group result in a compound called diamorphine (heroin)
• It 2 fold more active than morphine
6-diacetyl morphine
• To increase the level of morphine in the brain, some polar groups are masked.
• Acetylation of the hydroxy group at position 6 result in a compound called 6-diacetyl morphine.
• It is four times more active than morphine and more dangerous
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Oxycodone
• Modification at positions 3, 6 and 14 increases the analgesic activity than morphine
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N-phenylethylmorphine
Larger alkyl groups than methyl at nitrogen
position decreases the activity
The activity retained with larger groups such as
pentyl or hexyl
Groups like phenyethyl increases the activity
and suggest that there is a hydrophobic binding
site
Morphine antagonists
• The addition of an allyl and cyclopropyl to nitrogen side chain to oxymorphone result in a compounds without analgesic activity.
• They bind to morphine receptors and act as antagonists
• This useful in case of morphine overdose, morphine addict and alcoholism.
• Administering naloxone and nalorphine in morphine overdose, block morphine from binding to its receptor and prevent patient death from suffocation due to respiratory depression.
• Naltrexone used in case of morphine or heroin addict.
• Nalmephine used in case of alcoholism as block opioid receptors and prevent the release of endogenous opioids as a result of drinking.
• Nalorphine is antagonist at mu receptors and agonist at kappa receptors which provide a safe analgesia but it have undesirable side effects as hallucinogenic and psychosis due to activation of kappa receptors.
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Morphine antagonists
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• Removing ring E lead to loss in activity which mean that the basic nitrogen is important to activity
• Removing ring D lead to serious of compounds called morphinans
• levorphenol are more potent than morphine and with long duration of action but with more side effects
• Adding an allyl group gave an antagonist that is more potent than nalorphine
• Adding a phenylethyl group increases the potency than morphine
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Morphinans
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Benzomorphans
Removing ring C and D lead to a serious
of compounds called benzomorphans
Metazocine contains two cis methyl
groups that are important for analgesic
activity
Replacing N-methyl group of metazocine
with phenylethyl lead to phenazocine
with good analgesia and without
dependence
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Benzomorphans
Pentazocine has very potent analgesic activity and low risk of addiction. It act as
antagonist at mu receptors and agonist at kappa receptors. Also weak agonist at delta
receptors. The compound has serious side effects as hallucination and psychotomimetic
side effects
Bremazocine is with longer duration of action and more potency and does not depress
breathing
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Removing rings B, C and D lead to
compounds called 4-
phenylpiperidine
The activity is more than morphine
due to the ester group
Ketobemidone has more activity as
the ester changed to ketone
Pethidine (meperidine) has less
analgesic effect than morphine but
with rapid and short duration of
action. It can be used in childbirth
as it has less chance to depress
breathing of child due to short
duration of action
Replacing the methyl group of
pethidine with cinnamic acid
results in more potent analgesic
than morphine.
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Another type of opioid analgesics are 4-anilinopiperidine (Fentanyl and its analogues)
Very potent
They lack phenolic group, which suggest that phenolic group is not necessary for
analgesic activity while aromatic ring and basic nitrogen are essential
Are lipophilic, so they can cross BBB. Thus it can be used in surgery
Remifenatnyl with very short duration of action due to hydrolysis by esterases which
make it with less side effects.
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Removing rings B, C, D and E lead to the discovery of methadone
It is used as alternative for drug addiction for morphine and heroin
It is a diphenylpropylamine structure that contain an asymmetric center
One of the side effects of opioid analgesics is constipation
Linking methadone with 4-phenylpiperidine produce an antidiarrhoea agent (loperamide).
It act as selective agonist on opioid receptors in the GIT. It is lipophilic, slowly absorbed
and can be metabolized easily.
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Previous structures of morphine analogues are flexible molecules that may adopt many
conformations. In order to decrease these conformations, the strategy of rigidification had
been used to limit the number of conformations. This may increase selectivity, potency and
decrease side effects
Orvinols (oripavines) are type of compounds that has been used by this strategy
Examples of orvinols are etorphine, dihydroetorphine, diprenorphine and buprenorphine
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Etorphine is 10,000 times potency than morphine due to the lipophilic group at position
C20 which may increase the binding interactions with the receptors. It is used as to
immobilize large animals such elephants
Dihydroetorphine is 10 fold potency of etorphine.
Diprenorphine is a pure antagonist at mu receptors, due to addition of cyclopropyl group
at N-substituent. It is 100 times potent than nalorphine. It can be used to reverse the
effects of etorphine.
Buprenorphine is partial agonist at mu receptors and an antagonist at kappa and delta
receptors. It is more lipophilic than other orvinols. It has less side effects on respiration
Endogenous Opioid Peptides • Endogenous chemicals that interact with opioid receptors are enkephalins
• There are two types of enkephalins: Met-enkephalin and Leu-enkephalin
• Now there other peptides (neurotrasnsmitters or neurohormones) that act as neutral painkillers consist of 5-33 amino acids. These are:
enkephalin, the precursor is proenkephalin
Endorphin, the precursor is prodynorphin
Dynorphins, the precursor is pro-opiomelanocortin
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• Other endogenous peptides that had been discovered are:
nociceptin or orphanin-FQ
They are ligand for ORLI-receptor
They are heptadecapeptides and contain phenylalanine at N-terminal
Endomorphins
Are tetrapeptides that have affinity for mu receptors
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Endogenous Opioid Peptides
Binding of enkephalins
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• Enkephalins interact with two binding regions
• Phenol of tyrosine interact with T-binding region
• Phenyl ring of phenylalanine with P-binding region
• There is also the ionic-binding region
Message-address concept
• Enkephalins have preference to delta receptors
• Dynorphins have selectivity for kappa receptors
• Endorphins have selectivity for mu and delta receptors
• These differences in selectivity for analgesic receptors led to a theory called message-address concept
• It propose that part of the molecule is responsible for pharmacological activity (the message) and another part is responsible for target selectivity (the address).
• It could be a function group that can interact with one type of receptor
• It could a feature that can act as a steric shield and prevent the molecule from binding to some receptors but not the others
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Analogues of enkephalins and delta-selective opioids
• Enkephalin can be metabolized by peptidases between the bond of tyrosine and glycine
• To make enkephalin resistant to hydrolysis, analogues can be designed by:
replacing one or both of glycine units by D-amino acids such as
D-alanine
N-methylating the peptide bond can block peptidase hydrolysis
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Naltrindole is a selective antagonist of delta receptors
It is developed by fusing an aromatic ring to the C-ring of naltrexone a non-selective
delta antagonist.
The aromatic ring will act as the message for delta receptors
It is found that conformation that have adopted by leu-enkephalin (an endogenous
opioid) during interactions with delta receptor is similar to that of naltrindole