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Opiod Structure Activity Relationship

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Structure activity Relationship of Opiods

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Opiod Structure Activity Relationship

  1. 1. Structure Activity Relationship of Opioids Dr. Suji V. S. Dept of Pharmacology.
  2. 2. Classification of opiods based on structure Eg. Pentacyclic Morphines Codeine ,Buprenorphine, Oxycodone, Diacetylmorphine (Heroin) Tetracyclic Morphinan Levorphanol, butorphanol Tricyclic Benzazocine Pentazocine, Phenazocine Bicyclic Phenylpiperidine Meperidine
  3. 3. SAR Modification to Morphine
  4. 4. Chiral centers • Morphine has 5 Chiral centers. • Only the Levo(-) rotatory isomer is active
  5. 5. Biological action of opiods • depends on 1. Phenolic hydroxyl group 2. 6 hydroxyl 3. Double bond between 7 & 8 c 4. N-methyl group 5. Ether (E) bridge 6. Aromatic ring
  6. 6. Phenolic hydroxyl group • is needed for binding of μ & κ receptors; • seen in all potent µ agonist. • Changing -OH to just –H or -OCH3 lowers activity. R= C3 substituent Activity effect -H Decrease -OH Morphine -OCH3 (codeine) Decrease (1/3)
  7. 7. R= Nitrogen substituent Effect 3-5 Carbons (with double bond/ small cyclic or aromatic rings) eg. CH2CH=CH2 µ antagonist >5c (in chain or ring ) µ agonist Aralkyl CH2CH2Ph (Total 8 C) µ agonist (10X morphine) N-methyl group • Interacts hydrophobically with μ receptor. • Size of substituent on Nitrogen dictates potency and agonist/antagonist activity.
  8. 8. Opiod antagonists
  9. 9. 14 β H/OH moiety • Addition of OH at 14 β position 1. Increases activity (2-3X) 2. Increases penetration of BBB 3. Decrease in antitussive action
  10. 10. 7,8 double bond Reduction of 7,8 double bond increases activity Activity increases Activity increases OH at C14 7,8 Reduction of double bond to single bond
  11. 11. Hydroxyl at 6 • Modifications at 6 OH which increases activity 1. Removal of Hydroxyl at 6 increases lipophylicity 2. Oxidation of Hydroxyl to keto group at 6 + reduction of 7,8 double bond eg Hydrocodone 3. Acetylation of Hydroxyl at 6 (eg. Heroin) R= C6 substituent Effect in activity H Increase 10X =O (keto) =O (keto) with 7,8 reduction decrease (1/3) Increases (6X ) H3CC=O (acetyl) Increase
  12. 12. Hydrocodone Modifications at 6 OH which increases activity
  13. 13. Hydroxyl at 6 • Associated with mast cell degranulation  Histamine release  allergic response (eg . Codeine – so not given parentrally)
  14. 14. Ether linkage • Removal of Ether linkage produces compounds called Morphinans that has increased activity Activity increases No ether linkage Levorphanol (10X )
  15. 15. Morphinans- Levorphanol, Potency high Benzomorphine- Pentazocine Potency- low 4-Phenylpiperidines Mepiridine Potency low (1/10) Loss of other rings doesn’t effect analgesic activity. Aromatic rings
  16. 16. Morphine N- CH3, phenolic OH, B/C cis configuration potency & Selective μ agonism 6 αOH – Histamine release  decrease BP Lacks 14 β OH- no cough
  17. 17. Codeine • Methyl morphine (Weak µ agonist ) • OCH3  loss of activity  less potent (1/3) . Thus, used in mild to moderate pain only. • 6OH- release of Histamine  allergic responses. Thus not used parenterally. • Lack of 14 β OH- Used as antitussive drug • Metabolite is Morphine  abused by addicts
  18. 18. Heroin • Weak μ agonist • 3,6-diacetyl derivative of morphine • Two factors make it more potent than morphine a. Diacetyl form - increases its lipophilicity  enhances its penetration into brain b. Metabolite, 6 acetyl morphine, is more active than morphine These two factors work together to provide a intense and quick occuring ‘euphoric rush’ that addicts seek
  19. 19. Buprenorphine • Mixed Agonist/antagonist effect • N- cyclopropyl methyl group  μ antagonist overcome by • Additional hydrophobic & H bonding at C7 – High μ affinity  highly Potency (25X) – Highly lipid soluble  cross BBB
  20. 20. Pentazocine • Benzomorphine (tricyclic) • 1st agonist-antagonist to be used as analgesic (κ agonist & µ antagonist) • 5C N substitution  μ antagonist • Missing 6 &7 carbons  compromises its ability to interact with Receptors weak analgesic effect (1/5X)
  21. 21. Tramadol • Atypical opiod analgesic • • Dual action opiods (-) isomer blocks norepinephrine reuptake (+) isomer blocks serotonin reuptake  analgesic activity. But effect is weak • Metabolite is active - 1/35X
  22. 22. Naloxone • N-allyl nor oxy morphone • N –substituent CH2CH=CH2  Strong opiod antagonist
  23. 23. Phenylpiperidines
  24. 24. 4- Phenylpiperidines
  25. 25. Phenylpiperidines • Meperidine • Diphenoxylate 2 important congeners • Loperamide • are MOR agonists
  26. 26. Anilidopiperidines • Fentanyls/ Flexible opiods • Highly lipophylic  rapidly cross BBB  fast & potent albeit short lived analgesic response 4-(Phenyl propionamido)/ Anilido moiety
  27. 27. R1 • N- substituent • Potent, selective μ agonism R1 BBB penetration μ Receptor Affinity Phenethyl Thienyl ethyl Increased lipophilicity Increased Tetrazoline (polar) ↓pKa  ↓ratio of ionised- unionised form  better BBB penetration Decreased
  28. 28. R2 • Methoxy methyl moiety (Sulfentanyl, Alfentanyl) at C4 of piperidine ring 1. Lipophilic 2. Steric influence promotes high affinity to receptor
  29. 29. Meperidine/ Pethidine • 4-Phenylpiperidines • R3= Ethyl carboxylate ester • Potency- (1/10th)
  30. 30. Fentanyl • Anilidopiperidines • • R1 =Phenethyl N substitute 1. 80 times more potent than Morphine (both analgesia, resp depression)- 2. High lipid solubility  rapidly cross BBB- peak analgesia in 5min.
  31. 31. Thank you

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