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Opioid Analgesics

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

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  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. • 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

  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 Morphinans Benzomorphans 4-phenylpiperidines Methadone

  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 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

  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 Most strongly binds morphine Best bet for a safe analgesic

  22. 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+

  23. 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

  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

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