Morphine presentation
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Opioid drugs like morphine produce their pharmacological effects like analgesia by acting on neuronal cell membrane receptors. Morphine was first isolated in 1804 and is used to treat dull constant pain. It causes side effects like euphoria, nausea, constipation and respiratory depression due to binding to mu, kappa and delta opioid receptors in the brain and spinal cord. Several morphine analogs were developed as drugs, including codeine, heroin, methadone, levorphanol, fentanyl, dipipanone, sufentanil and tapentadol, by modifying functional groups on morphine. These analogs have varying degrees of potency and side effect profiles compared to morphine.
Morphine presentation
- 2. Opioid drugs, typified by morphine, produce their pharmacological actions, including analgesia, by acting on receptors located on neuronal cell membranes.
- 3. Morphine (1804): 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.
- 4. Why it gives feelings of Euphoria and causes addiction? There are different types of Opioid Receptors, Its action depends on the type of receptor morphine binds to…
- 5. Receptor type Location Effects 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 Brain Analgesia, dependence
- 7. Now, Let’s see together the effect of masking or removing functional groups on activity… 1- The Phenol Moiety: Masking the phenol group resulted in decreased activity, thus it is crucial for activity. R=H Morphine R=Me Codeine Codeine 20% active (injected peripherally) 0.1% active (injected into brain) NMe O RO HO H H
- 8. 2- The 6-alcohol: •Activity increases due to reduced polarity •Compounds cross the blood brain barrier more easily •6-OH is not important for binding NMe O HO HO NMe O HO O NMe O HO
- 9. R=Ac 6-Acetylmorphine Increased activity (4x) •Acetyl masks a polar alcohol group making it easier to cross BBB •Phenol group is free and molecule can bind immediately •Dependence is very high •6-Acetylmorphine is banned in many countries NMe O HO RO H H
- 10. 3- The Double Bond at 7,8: Dihydromorphine Increased activity The alkene group is not important to binding. NMe O HO HO H H
- 11. 4- The 3o Amine: No activity Nitrogen is essential to binding. CHMe O HO HO H H
- 12. NR= NH Normorphine Reduced activity (25%) NR= N+Me2 No activity •Normorphine is more polar and crosses the BBB slowly •Note: R affects whether the analogue is an agonist (axial and reaching to agonist site) or an antagonist (equatorial and reaching to antagonist site), rigidification could be applied to stabilize such conformations. •Optimum distance between 3 o amine and phenyl ring is essential for activity. NR O HO HO H H
- 13. Important Binding Interactions: HBD or HBA Ionic (N is protonated) van der Waals NMe O HO HO H H
- 14. Morphine analogsavailable as drugs: 1- Codeine (1832): How it’s related: Methyl ether of morphine. Activity: 20% that of morphine. Treats: Moderate pain, Coughs, diarrhea.
- 15. 2- Heroin (1874): How it’s related: 3,6-diacetyl ester of morphine. Activity: 2x that of morphine as it is easier to cross BBB. Treats: Pain in terminally ill patients. Side effects: Euphoria, addiction, tolerance.
- 16. 5- Methadone(1937): How its related: Rings B,C,D,E opened. Activity: Less than Morphine. Used to: Treat addiction. Advantages: Can be given orally, Less side effects.
- 17. 3- Levorphanol (1948): 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.
- 18. 4- Fentanyl (1960): 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 route (IV, oral, transdermal, buccal). Used for: Anesthesia and Chronic pain management Side effects: Sudden respiratory depression, More addictive than heroin, Less euphoria, more sedation.
- 19. 8- Dipipanone (1970): How it’s related: Rings B,C,D opened. Activity: Similar to morphine. Used for: Patients allergic to morphine. Side effects: Sudden respiratory depression, risk of abuse.
- 20. 6- Sufentanil (1974): How it’s related: Rings B,C,D removed. Activity: 500x that of morphine Advantages: Strongest Pain killer available for humans. Used for: in surgery and post-operative pain management for patients that are heavily Opioid tolerant because of long term opiate use. Side effects: Sudden respiratory depression, anaphylaxis in rare cases.
- 21. 7-Tapentadol (2008): How it’s related: Rings B,C,D removed. Activity: Weak μ agonist and inhibit the reuptake of norepinephrine (similar to Tramadol). Advantages: Less side effects. Used for: Indicated for controlling the pain of diabetic neuropathy. Side effects: Dependence and addiction.
- 22. References: 1-The Annals of Pharmacotherapy: Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain, by: Celene M. Amabile, Bill J. Bowman. 2- Bioorganic & Medicinal Chemistry: Design, synthesis, and structure–activity relationship of novel opioid κ- agonists, by: Koji Kawai et al. 3- Indian J Anaesth.: Sufentanil Vs Fentanyl for Fast-Track Cardiac Anaesthesia, by: C M Deshpande et al. 4- Expert Opinion on Pharmacotherapy: Mechanistic and functional differentiation of tapentadol and tramadol, by: Robert B Raffa, Helmut Buschmann.