Opioid Analgesics

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Opioid Analgesics

• Mallika Doss
• April 10, 2008

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Overview

• History
• Morphine
• SAR of Morphine
• Drug Dissection of Morphine
• Morphine Analogues
• Opioid Receptors Receptor Binding
• Agonists and Antagonists
• Why you feel happy ?
• Endogenous Opioid peptides
• The Future

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The History

• First use in Mesopotamia
• First recorded use in China
• 632 AD Opium reaches Spain, Persia, and India
• 17th century Tobacco comes to China
• 1644 Chinese emperor bans tobacco
• 19th century China closes its doors to the
  world
• Deprived of tobacco, Chinese people start smoking
  opium!
• Opium production in China couldnt keep up with
  demand. British East India company sees
  opportunity.
• 1830s 1 million of opium smuggled into China
  via Port Canton.

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The History

• Chinese authorities burnt down the port British
  traders outraged.
• 1839-42 Opium Wars Chinese were defeated and
  forced to lease trading port to Britain.
• 19th century Opium dens common in Britain.
• 1882 Addictive properties of opium discovered
  but largely ignored.
• 1909 IOC set up to curb opium production
• 1924 Opium production went underground

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Morphine

• Named after the Greek God, Morpheus (God of
  dreams)
• Good for treating dull, constant pain rather than
  sharp, periodic pain
• Side effects
• Excitation
• Euphoria
• Nausea
• Pupil constriction
• Constipation
• Tolerance and Dependence
• Depression of breathing

Maximize
Minimize
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Morphine - SAR
Phenolic OH ?
? Aromatic ring
Required
Required
? N-methyl group
Ether bridge ?
Required
Not Required
? Double bond at 7-8
6-alcohol ?
Not Required
Not Required
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Morphine Drug Dissection
Loss of activity
E
Activity retained
D
B
C
Morphinans
Benzomorphans
4-phenylpiperidines
Methadone
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Morphine Analogues - Codeine

• How its related
• Methyl ether of morphine
• Activity
• 20 that of morphine
• Pro-drug of morphine
• Metabolized by O-demethylation in the liver to
  make morphine

Codeine
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Morphine Analogues - Codeine

• Treats
• Moderate pain
• Coughs
• diarrhea
• Marketed as
• Tylenol with Codeine
• Hydrocodone
• Vicodin (with Thebaine)

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Morphine Analogues - Heroine

• How its related
• 3,6-diacetyl ester of morphine
• Activity
• 2x that of morphine
• Polar groups are hidden, making it easy to cross
  BBB.
• Treats
• Pain in terminally ill patients
• Side effects
• Euphoria, addiction, tolerance
• Marketed as
• Heroin, dope

Heroine
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Morphine Analogues - Heroine

• 6-acetylmorphine
• How its related
• 6-acetyl of morphine
• Activity
• 4x that of morphine!
• Polarity decreased, but phenol is ready to bind
  receptor
• Side effects Very potent!!
• Euphoria, addiction, etc.
• Marketed as
• NOTHING! Its banned from production in many
  countries

6-acetylmorphine
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Morphine Analogues - Morphinans

• How its related
• Ether bridge removed
• Activity
• 5x that of morphine
• Advantage
• It can be taken orally
• Lasts longer
• Easier to synthesize
• Side effects
• High toxicity, comparable dependence
• Marketed as
• Levo-Dromoran

Levorphanol
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Morphine Analogues - Benzomorphans

• How its related
• Rings C and D removed
• Activity
• 4x that of morphine
• Advantages
• No addictive properties
• Does not depress breathing
• Lasts longer
• Side effects
• Hallucinogenic
• Marketed as
• Prinadol, Norphen
• Fortal, Talwin NX

Phenazocine
Pentazocine
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Morphine Analogues 4-phenylpiperidines

• Fentanyl
• How its related
• Rings B,C,D removed
• Activity
• 100x that of morphine
• Advantages
• Cross BBB efficiently
• Really easy to make
• Rapid onset, short duration
• Can be administered any way (IV, oral,
  transdermal, buccal)

Fentanyl
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Morphine Analogues 4-phenylpiperidines

• Used for
• Anesthesia
• Chronic pain management
• Side effects
• Sudden respiratory depression
• More addictive than heroin
• Less euphoria, more sedation
• Marketed as
• Sufenta (used in ? surgery)
• Carfentanil (used in vet practice)
• Percopop, OxyContin, magic (heroin/cocaine)

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Morphine Analogues - Methadone

• How its related
• Rings B,C,D,E opened
• Activity
• lt Morphine
• Used to
• Ween addicts off heroine or morphine
• Advantages
• Can be given orally
• Less severe side effects
• Marketed as
• Dolophine, Amidone, Methadose

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Morphine analogues - Naltrexone

• How its related
• Cyclopropylmethylene added to morphine
• Activity
• None?!
• Morphine antagonists
• Used to treat
• Morphine overdose
• Heroin addicts post-rehab
• Advantages
• No side effects
• Marketed as
• Revia, Depade, Vivitrol

Naltrexone
Nalorphine
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Agonists and Antagonists
Equatorial Antagonist binding area
Axial Agonist binding area
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SIDE NOTE

• Other factors important to receptor binding
• Stereochemistry
• Enantiomers of many of the analogues were tested
  for analgesic activity. Overall, they didnt have
  any.
• Rigidification
• Used to maintain active formation and eliminate
  alternative conformations
• Increases selectivity for receptors

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Opioid Receptors

• Receptor-binding motif
• Phenol OH
• Aromatic ring
• Amine group

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Opioid Receptors
Most strongly binds morphine
Receptor type Location Effects
µ Brain, spinal cord Analgesia, Respiratory depression, euphoria, addiction, ALL pain messages blocked
? Brain, spinal cord Analgesia, sedation, all non-thermal pain messages blocked
d Brain Analgesia, antidepression, dependence
Best bet for a safe analgesic
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Receptor binding - µ

• Opening of the K channel hyperpolarizes the
  membrane
• Action potential not sent
• Ca2 not released
• Reduces neurotransmitter release

Morphine
µ
K
K
Hyper-polarized!
K
K
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Receptor Binding - ?

• Binding causes closing of Ca2 channels
• Neurotransmitters not released
• Pain message not sent

Morphine
?
Ca2
Ca2
Ca2
Ca2
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Why you feel happy
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Why you feel happy

• Heroin modifies the action of dopamine in the
  brain.
• Once crossing the blood-brain barrier, heroin is
  converted to morphine, which acts as an agonist.
• This binding inhibits the release of GABA from
  the nerve terminal, reducing the inhibitory
  effect of GABA on dopaminergic neurones.
• The increased activation of dopaminergic neurones
  and the release of dopamine into the synaptic
  cleft results in activation of the post-synaptic
  membrane.
• Continued activation of the dopaminergic reward
  pathway leads to the feelings of euphoria and the
  high associated with heroin use.

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Endogenous Opioid Peptides

• Your bodys natural painkillers
• Have a preference for the d-receptor
• Alternative method of pain relief ? inhibit the
  peptidases that degrade them ? thiorphan (still
  new)
• 3 types of EOPs
• Enkephalins
• Dynorphins
• Endorphins

Met-enkephalin
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The Future

• Find an agonist that solely binds to the
  ?-receptor
• Explore the µ-receptor subtypes further to see if
  any of them dont cause harmful side effects
• Peripheral opiate receptors avoid BBB obstacle
• Block postsynaptic receptors involved in the
  transmission of a pain signal
• GABA
• Agonists for the cannabinoid receptor

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References