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Opioid Analgesics - PowerPoint

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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
• 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 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
        • Named after the Greek God,
          Morpheus (God of dreams)
        • Good for treating dull, constant pain
          rather than sharp, periodic pain
        • Side effects:
           – Excitation
                            Maximize
           – Euphoria
           – Nausea
           – Pupil constriction
           – Constipation
           – Tolerance and Dependence
Minimize
           – Depression of breathing
           Morphine - SAR
Phenolic OH 
  Required           Aromatic ring
                           Required
                          N-methyl group
  Ether bridge 
                             Required
 Not Required


 6-alcohol         Double bond at 7-8
Not Required            Not Required
    Morphine – Drug Dissection

Activity retained                   E     Loss of activity

                        D       B

                            C


                    Benzomorphans
                    Morphinans
                    Methadone
                    4-phenylpiperidines
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 - Codeine
              • Treats:
                 – Moderate pain
                 – Coughs
                 – diarrhea
              • Marketed as:
                 – Tylenol® with Codeine
                 – Hydrocodone
                 – Vicodin® (with
                   Thebaine)
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.
   Heroine   • Treats:
                – Pain in terminally ill patients
             • Side effects
                – Euphoria, addiction, tolerance
             • Marketed as:
                – Heroin, “dope”
Morphine Analogues - Heroine
                  6-acetylmorphine
                  • How it‟s related:
                     – 6-acetyl of morphine
                  • Activity
                     – 4x that of morphine!
                  • Polarity decreased, but phenol is
 6-acetylmorphine   ready to bind receptor
                  • Side effects: Very potent!!
                     – Euphoria, addiction, etc.
                  • Marketed as:
                     – NOTHING! It‟s banned from
                       production in many countries
Morphine Analogues - Morphinans
              • How it‟s related:
                 – Ether bridge removed
              • Activity:
                 – 5x that of morphine
              • Advantage:
                 – It can be taken orally
Levorphanol      – Lasts longer
                 – Easier to synthesize
              • Side effects:
                 – High toxicity, comparable dependence
              • Marketed as
                 – Levo-Dromoran®
             Morphine Analogues -
•
                  Benzomorphans
    How it‟s related                   Phenazocine
     – 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
                    Fentanyl
                    • How it‟s related:
                       – Rings B,C,D removed
                    • Activity:
Fentanyl
                       – 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)
        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
         • 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
• How it‟s related:
   – Cyclopropylmethylene added
     to morphine
• Activity:
   – None?!
• Morphine antagonists
• Used to treat:                      Naltrexone
   – Morphine overdose
   – Heroin addicts post-rehab
• Advantages:
   – No side effects
• Marketed as:                    Nalorphine
   – Revia, Depade, Vivitrol
Agonists and Antagonists
                               Equatorial Antagonist
                                  binding area




  Axial Agonist binding area
                  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
          • Receptor-binding
            motif:
             – Phenol OH
             – Aromatic ring
             – Amine group
                   Opioid Receptors
  Most
             Receptor Location      Effects
strongly       type
 binds
morphine
               μ      Brain,
                      spinal cord
                                    Analgesia, Respiratory
                                    depression, euphoria, addiction,
 Best bet                           ALL pain messages blocked
for a safe
analgesic      κ      Brain,
                      spinal cord
                                    Analgesia, sedation, all non-
                                    thermal pain messages blocked



               δ      Brain         Analgesia, antidepression,
                                    dependence
  Receptor binding - μ
                        • Opening of the K+
Morphine                channel
                        hyperpolarizes the
                        membrane
                        •Action potential not
  μ                     sent
                        •Ca+2 not released
                        •Reduces
            Hyper-      neurotransmitter
           polarized!
                        release
  Receptor Binding - κ
                • Binding causes
Morphine        closing of Ca+2
                channels
                • Neurotransmitters
                not released
  κ             • Pain message not
                sent
Why you feel “happy”
           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
• Your body‟s natural
  painkillers
• Have a preference for the δ-
  receptor
• Alternative method of pain
  relief  inhibit the         Met-enkephalin
  peptidases that degrade
  them  thiorphan (still new)
• 3 types of EOPs:
   – Enkephalins
   – Dynorphins
   – Endorphins
                    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
References

				
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