opioid analgesics - جامعة نزوى · •opiates are narcotic analgesics that are related to...

Opioid Analgesics

Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 623 1

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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Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 636 8

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

Patrick G L. Introduction to Medicinal Chemistry. 2013. p. 634-635 9

• 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