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Opioid Analgesics. Mallika Doss April 10, 2008. 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. The History.

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opioid analgesics

Opioid Analgesics

Mallika Doss

April 10, 2008

overview
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
the history
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 couldn’t keep up with demand. British East India company sees opportunity.
  • 1830s – £1 million of opium smuggled into China via Port Canton.
the history4
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
morphine
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

morphine sar
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

morphine drug dissection
Morphine – Drug Dissection

Loss of activity

Activity retained

E

D

B

C

Morphinans

Benzomorphans

4-phenylpiperidines

Methadone

morphine analogues codeine
Morphine Analogues - Codeine
  • How it’s 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

morphine analogues codeine9
Morphine Analogues - Codeine
  • Treats:
    • Moderate pain
    • Coughs
    • diarrhea
  • Marketed as:
    • Tylenol® with Codeine
    • Hydrocodone
    • Vicodin® (with Thebaine)
morphine analogues heroine
Morphine Analogues - Heroine
  • How it’s 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

morphine analogues heroine11
Morphine Analogues - Heroine

6-acetylmorphine

  • How it’s 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! It’s banned from production in many countries

6-acetylmorphine

morphine analogues morphinans
Morphine Analogues - Morphinans
  • How it’s 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

morphine analogues benzomorphans
Morphine Analogues - Benzomorphans

Phenazocine

  • How it’s 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

Pentazocine

morphine analogues 4 phenylpiperidines
Morphine Analogues – 4-phenylpiperidines

Fentanyl

  • How it’s 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

morphine analogues 4 phenylpiperidines15
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)
morphine analogues methadone
Morphine Analogues - Methadone
  • How its related:
    • Rings B,C,D,E opened
  • Activity
    • < Morphine
  • Used to:
    • Ween addicts off heroine or morphine
  • Advantages:
    • Can be given orally
    • Less severe side effects
  • Marketed as
    • Dolophine®, Amidone®, Methadose®
morphine analogues naltrexone
Morphine analogues - Naltrexone
  • How it’s 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

agonists and antagonists
Agonists and Antagonists

Equatorial Antagonist binding area

Axial Agonist binding area

side note
SIDE NOTE:
  • Other factors important to receptor binding:
    • Stereochemistry
      • Enantiomers of many of the analogues were tested for analgesic activity. Overall, they didn’t have any.
    • Rigidification
      • Used to maintain active formation and eliminate alternative conformations
      • Increases selectivity for receptors
opioid receptors
Opioid Receptors
  • Receptor-binding motif:
    • Phenol OH
    • Aromatic ring
    • Amine group
opioid receptors21
Opioid Receptors

Most strongly binds morphine

Best bet for a safe analgesic

receptor binding
Receptor binding - μ
  • Opening of the K+ channel hyperpolarizes the membrane
  • Action potential not sent
  • Ca+2 not released
  • Reduces neurotransmitter release

Morphine

μ

K+

K+

Hyper-polarized!

K+

K+

receptor binding23
Receptor Binding - κ
  • Binding causes closing of Ca+2 channels
  • Neurotransmitters not released
  • Pain message not sent

Morphine

κ

Ca+2

Ca+2

Ca+2

Ca+2

why you feel happy25
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.
endogenous opioid peptides
Endogenous Opioid Peptides
  • Your body’s natural painkillers
  • Have a preference for the δ-receptor
  • Alternative method of pain relief  inhibit the peptidases that degrade them  thiorphan (still new)
  • 3 types of EOPs:
    • Enkephalins
    • Dynorphins
    • Endorphins

Met-enkephalin

the future
The Future
  • Find an agonist that solely binds to the κ-receptor
  • Explore the μ-receptor subtypes further to see if any of them don’t 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