Opioids SAR 1

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kyleannkelsey
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269310
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Opioids SAR 1
Updated:
2014-04-05 12:40:22
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Opioids SAR
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Opioids SAR 1
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Opioids SAR 1
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  1. Morphine is what type of opioid?
    Multicyclic

  2. All clinically active opioid analgetics and antagonists have what pharamcophore?
    4-phenylpiperidine
  3. Morphine has an amphorteric, lipophic or hydrophilic pharamcophore?
  4. Amphoteric
    • pKa of the basic amine = 8
    • pKa of the acidic phenol = 11

  5. Morphine exists predominantly in an ionic or non-ionic form at pH 7.4?
    • Both
    • Ionic: protonated amine
    • Phenol: almost completely unionized

  6. Morphine is a relatively polar or non-polar structure?
    Polar
  7. What is the Log P of morphine?
    0.15
  8. Morphine is relatively lipophilic or hydrophilic?
    • Hyrdophilic
    • (low lipophilicity)
  9. Other than morhine, all other opioids have higher or lower Log P values?
    Higher
  10. When crossing the BBB, is a high Log P more or less advantageous?
    More
  11. When crossing the BBB, is a low Log P more or less advantageous?
    Less
  12. A low log P indicates lipophilicity of hydrophilicity?
    Hydrophilicity
  13. A high log P indicates lipophilicity of hydrophilicity?
    Lipophilicity
  14. What are the common metabolic pathways that opioids are involved in?
    • N-dealkylation
    • O-dealkylation
    • Hydrolysis
    • Phase II conjugation at C3
    • Phase II conjugation at C6

  15. The N-dealkylated form of N-methylated opioids like Morphine is called what?
    Nor-derivative

  16. Nor-derivatives of N-methylated opioids like morphine are active or inactive?
    • Active but less so than the parent structure
    • Because Less lipophilic
    • Loses the ability to interact with the hydrophobic agonist site on the mu receptor
    • Poorer BBB penetration

  17.  Why is morphine less active in the nor-derivative form?
    • Less lipophilic
    • Loses the ability to interact with the hydrophobic agonist site on the mu receptor
    • Poorer BBB penetration
  18. What enzyme catalyzes the N-dealkylation reaction?
    CYP3A4

  19. What is this drug?
    Morphine

  20. O-dealkylation of C3 ethers creates an active or inactive metabolite?
    • Activates Codeine
    • Necessary for Analgesic acitivty

  21.  What enzyme activates codeine through an O-dealkylation of the C3 ether?
    CYP2D6

  22.  Is a phenolic OH group at C3 essential for binding multicyclic opioids to mu and kappa receptors?
    Yes, must be free (not an ether)

  23. Hydrolysis of C3-esters creates an active or inactive metabolite?
    • Active
    • C3 must be free for analgesic activity

  24. What drug is a C3 ester opioid?
    Heroin (the 3,6-diacetyl ester analog of morphine)

  25. Phase II conjugation at C3 are active or inactive metabolites?
    • Inactive
    • No free C3 OH

  26. What types of conjugates are formed at the C3 OH of opioids?
    Glucuronic acid or sulfate
  27. What metabolites of multicyclic opiods would you find in the urine?
    • Glucuronic acid or sulfate conjugates

  28. What types of conjugates are formed at the C6 OH of opioids?
    Glucuronic acid

  29.  A C6 glucuronide of Morphine is inactive or active?
    Active, has a higher affinity for mu receptors than the free alcohol

  30. What metabolite of morphine is believed to be responsible for a significant amount of morphine’s analgetic action?
    C6-OH glucoronide

  31. The C6-OH glucoronide metabolite of morphine is excreted quickly or slowly and why?
    • Quickly
    • Because it is highly ionized
  32. How many asymmetric centers does Morphine have and what are they?
    • 5
    • = 5, 6, 9, 13, 14
  33. What is the stereochemistry of naturally occurring levorotatory (-) morphine ( the most active at the receptors)?
    5R,6S,9R,13S,14R
  34. Which stereocenter of morphine can invert and still retain its activity (5R,6S,9R,13S,14R)?
    C14 can be 14S
  35. Is morphine in the following configuration active: 5R,6S,9R,13R,14R
    No, should be: 5R,6S,9R,13S,14R
  36. Is morphine in the following configuration active: 5R,6S,9R,13S,14S
    • Yes, C14 is the only stereocenter that can invert
    • Natural morphine is: 5R,6S,9R,13S,14R
    • Activity of this isomer is 10x less than the 14R isomer
  37. Is morphine in the following configuration active: 5R,6S,9R,13S,14R
    Yes
  38. Is morphine in the following configuration active: 5R,6S,9S,13R,14R
    No, should be: 5R,6S,9R,13S,14R
  39. Ring C is forced into a ____________ conformation due to the presence of the 7,8-double bond and the restraining furan (E) ring.
    pseudo-boat

  40. Where is the A ring?

  41. Where is the B ring?

  42. Where is the C ring?

  43. Where is the D ring?

  44. Where is the E ring?
  45. The C ring is most active in what conformation?
    Chair
  46. What is the conformation of the B/C ring fusion in naturally occurring levorotatory (-) morphine?
    • Cis
    • (right angles to one another, creating a non-planar structure)

  47. How is the cis B/C ring conformation in naturally occurring levorotatory (-) morphine indicated?
    By a solid line at the C14-H (coming out of the paper)

  48.  A C14 with an H pointing away from you (dotted line) indicates what?
    • 14R configuration
    • Lower analgesic potency
    • Alpha configuration
    • Trans B/C ring fusion

  49.  A C14 with an H pointing toward you (solid line) indicates what?
    • 14S configuration
    • Normal analgesic potency
    • Beta configuration
    • Cis B/C ring fusion

  50. When the B/C ring fusion is cis, what will the C/D ring fusion be?
    • Trans
    • Co-planar
  51. What is a morphinan?
    • Opioids that have four rings

  52. A Morphinan in a 14S configuration will have what effect on activity compared to the 14R version?
    2 fold decrease
  53. With either the B/C-cis or the B/C-trans opioids, only the ___________ isomers have the proper stereochemistry to bind to receptors and evoke analgesic activity.
    levorotatory (-)
  54. The __________________ opioid isomers are clinically inactive as analgetics.
    Dextrorotatory (+)
  55. Dextrorotatory isomers of mu opioid analgetics retain ____________ action.
    Antitussive
  56. The ____________________ structure gives opioid drugs their analgetic activity.
    • 4-phenylpiperidine

  57.  What is the significance of the orientation of the phenyl ring?
    • Essential
    • Will dictate which of the two mu receptor Van der Waals (TRP) sites the opioid will bind

  58.  Can the phenyl ring change conformation in all multicyclic opioids?
    No

  59. What is the orientation of the phenyl ring relative to the piperidine ring (D ring) in all multicyclic opioids?
    Axial

  60.  Is the phenyl ring essential?
    Yes

  61. What part of the receptor does the phenyl ring bind to in all multicyclic opioids?
    TRP – one of the Van der Waals sites

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