1. Opioid Analgesics Mallika Doss April 10, 2008

2. Overview HistoryHistory MorphineMorphine –SAR of Morphine –Drug Dissection of Morphine Morphine AnaloguesMorphine Analogues Opioid Receptors & Receptor BindingOpioid Receptors & Receptor Binding Agonists and AntagonistsAgonists and Antagonists Why you feel “happy”Why you feel “happy” Endogenous Opioid peptidesEndogenous Opioid peptides The FutureThe Future

3. The History First use in MesopotamiaFirst use in Mesopotamia First recorded use in ChinaFirst recorded use in China 632 AD – Opium reaches Spain, Persia, and India632 AD – Opium reaches Spain, Persia, and India 17 th century – Tobacco comes to China17 th century – Tobacco comes to China 1644 – Chinese emperor bans tobacco1644 – Chinese emperor bans tobacco 19 th century – China closes its doors to the world19 th century – China closes its doors to the world Deprived of tobacco, Chinese people start smoking opium!Deprived of tobacco, Chinese people start smoking opium! Opium production in China couldn’t keep up with demand. British East India company sees opportunity.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.1830s – £1 million of opium smuggled into China via Port Canton.

4. The History Chinese authorities burnt down the port; British traders outraged.Chinese authorities burnt down the port; British traders outraged. 1839-42 – Opium Wars; Chinese were defeated and forced to lease trading port to Britain.1839-42 – Opium Wars; Chinese were defeated and forced to lease trading port to Britain. 19 th century – Opium dens common in Britain.19 th century – Opium dens common in Britain. 1882 – Addictive properties of opium discovered but largely ignored.1882 – Addictive properties of opium discovered but largely ignored. 1909 – IOC set up to curb opium production1909 – IOC set up to curb opium production 1924+ – Opium production went underground1924+ – 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  6-alcohol   Double bond at 7-8  N-methyl group  Aromatic ring Ether bridge  Required Not Required Required Required

7. Morphine – Drug Dissection E D Loss of activity Activity retained C B MorphinansBenzomorphans4-phenylpiperidinesMethadone

8. Morphine Analogues - Codeine How it’s relatedHow it’s related –Methyl ether of morphine ActivityActivity –20% that of morphine Pro-drug of morphinePro-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:How it’s related: –3,6-diacetyl ester of morphine Activity:Activity: –2x that of morphine Polar groups are hidden, making it easy to cross BBB.Polar groups are hidden, making it easy to cross BBB. Treats:Treats: –Pain in terminally ill patients Side effectsSide effects –Euphoria, addiction, tolerance Marketed as:Marketed as: –Heroin, “dope” Heroine

11. Morphine Analogues - Heroine 6-acetylmorphine How it’s related:How it’s related: –6-acetyl of morphine ActivityActivity –4x that of morphine! Polarity decreased, but phenol is ready to bind receptorPolarity decreased, but phenol is ready to bind receptor Side effects: Very potent!!Side effects: Very potent!! –Euphoria, addiction, etc. Marketed as:Marketed as: –NOTHING! It’s banned from production in many countries 6-acetylmorphine

12. Morphine Analogues - Morphinans How it’s related:How it’s related: –Ether bridge removed Activity:Activity: –5x that of morphine Advantage:Advantage: –It can be taken orally –Lasts longer –Easier to synthesize Side effects:Side effects: –High toxicity, comparable dependence Marketed asMarketed as –Levo-Dromoran® Levorphanol

13. Morphine Analogues - Benzomorphans How it’s relatedHow it’s related –Rings C and D removed ActivityActivity –4x + that of morphine AdvantagesAdvantages –No addictive properties –Does not depress breathing –Lasts longer Side effectsSide effects –Hallucinogenic Marketed asMarketed as –Prinadol, Norphen –Fortal, Talwin NX Pentazocine Phenazocine

14. Morphine Analogues – 4- phenylpiperidines Fentanyl How it’s related:How it’s related: –Rings B,C,D removed Activity:Activity: –100x that of morphine Advantages: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:Used for: –Anesthesia –Chronic pain management Side effects:Side effects: –Sudden respiratory depression –More addictive than heroin –Less euphoria, more sedation Marketed as:Marketed as: –Sufenta (used in ♥ surgery) –Carfentanil (used in vet practice) –“Percopop”, OxyContin, “magic” (heroin/cocaine)

16. Morphine Analogues - Methadone How its related:How its related: –Rings B,C,D,E opened ActivityActivity –< Morphine Used to:Used to: –Ween addicts off heroine or morphine Advantages:Advantages: –Can be given orally –Less severe side effects Marketed asMarketed as –Dolophine®, Amidone®, Methadose®

17. Morphine analogues - Naltrexone How it’s related:How it’s related: –Cyclopropylmethylene added to morphine Activity:Activity: –None?! Morphine antagonistsMorphine antagonists Used to treat:Used to treat: –Morphine overdose –Heroin addicts post-rehab Advantages:Advantages: –No side effects Marketed as:Marketed as: –Revia, Depade, Vivitrol Nalorphine Naltrexone

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

19. SIDE NOTE: Other factors important to receptor binding:Other factors important to receptor binding: –Stereochemistry Enantiomers of many of the analogues were tested for analgesic activity. Overall, they didn’t have any.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 conformationsUsed to maintain active formation and eliminate alternative conformations Increases selectivity for receptorsIncreases selectivity for receptors

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

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

22. Receptor binding - μ Morphine Opening of the K + channel hyperpolarizes the membrane Opening of the K + channel hyperpolarizes the membrane Action potential not sentAction potential not sent Ca +2 not releasedCa +2 not released Reduces neurotransmitter releaseReduces neurotransmitter release Hyper- polarized! μ

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

24. Why you feel “happy”

25. Heroin modifies the action of dopamine in the brain.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.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.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.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. 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 painkillersYour body’s natural painkillers Have a preference for the δ- receptorHave a preference for the δ- receptor Alternative method of pain relief  inhibit the peptidases that degrade them  thiorphan (still new)Alternative method of pain relief  inhibit the peptidases that degrade them  thiorphan (still new) 3 types of EOPs:3 types of EOPs: –Enkephalins –Dynorphins –Endorphins Met-enkephalin

27. The Future Find an agonist that solely binds to the κ-receptorFind 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 effectsExplore the μ-receptor subtypes further to see if any of them don’t cause harmful side effects Peripheral opiate receptors – avoid BBB obstaclePeripheral opiate receptors – avoid BBB obstacle Block postsynaptic receptors involved in the transmission of a pain signalBlock postsynaptic receptors involved in the transmission of a pain signal GABAGABA Agonists for the cannabinoid receptorAgonists for the cannabinoid receptor

28. References