1. Opioid Analgesics
Mallika Doss
April 10, 2008

2. 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

3. 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.

4. The History
Chinese authorities burnt down the port; British traders outraged.
– 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

5. 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

6. 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

7. Morphine – Drug Dissection
Loss of activity
Activity retained E D B C
Methadone
4-phenylpiperidines
Benzomorphans
Morphinans

8. 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

9. Morphine Analogues - Codeine
Treats:
Moderate pain
Coughs
diarrhea
Marketed as:
Tylenol® with Codeine
Hydrocodone
Vicodin® (with Thebaine)

10. 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

11. 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

12. 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

13. Morphine Analogues - Benzomorphans
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
Phenazocine
Pentazocine

14. 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

15. 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)

16. 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®

17. 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

18. Agonists and Antagonists
Equatorial Antagonist binding area
Axial Agonist binding area

19. 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

20. Opioid Receptors Receptor-binding motif: Phenol OH Aromatic ring
Amine group

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

22. Receptor binding - μ μ K+ K+ K+ K+
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+

23. Receptor Binding - κ κ Ca+2 Ca+2 Ca+2 Ca+2
Binding causes closing of Ca+2 channels
Neurotransmitters not released
Pain message not sent
Morphine κ
Ca+2
Ca+2
Ca+2
Ca+2

24. Why you feel “happy”

25. 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.

26. 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

27. 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

28. References