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Opioids SAR 1

The flashcards below were created by user kyleannkelsey on FreezingBlue Flashcards.

  1. Morphine is what type of opioid?
    Multicyclic
  2. Image Upload 1
    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
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    Morphine exists predominantly in an ionic or non-ionic form at pH 7.4?
    • Image Upload 3
    • Both
    • Ionic: protonated amine
    • Phenol: almost completely unionized
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    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
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    The N-dealkylated form of N-methylated opioids like Morphine is called what?
    Nor-derivative
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    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
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     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. Image Upload 8
    What is this drug?
    Morphine
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    O-dealkylation of C3 ethers creates an active or inactive metabolite?
    • Activates Codeine
    • Necessary for Analgesic acitivty
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     What enzyme activates codeine through an O-dealkylation of the C3 ether?
    CYP2D6
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     Is a phenolic OH group at C3 essential for binding multicyclic opioids to mu and kappa receptors?
    Yes, must be free (not an ether)
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    Hydrolysis of C3-esters creates an active or inactive metabolite?
    • Active
    • C3 must be free for analgesic activity
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    What drug is a C3 ester opioid?
    Heroin (the 3,6-diacetyl ester analog of morphine)
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    Phase II conjugation at C3 are active or inactive metabolites?
    • Inactive
    • No free C3 OH
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    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?
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    • Glucuronic acid or sulfate conjugates
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    What types of conjugates are formed at the C6 OH of opioids?
    Glucuronic acid
  29. Image Upload 18
     A C6 glucuronide of Morphine is inactive or active?
    Active, has a higher affinity for mu receptors than the free alcohol
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    What metabolite of morphine is believed to be responsible for a significant amount of morphine’s analgetic action?
    C6-OH glucoronide
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    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?
    • Image Upload 21
    • 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
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    Where is the A ring?
    Image Upload 23
  41. Image Upload 24
    Where is the B ring?
    Image Upload 25
  42. Image Upload 26
    Where is the C ring?
    Image Upload 27
  43. Image Upload 28
    Where is the D ring?
    Image Upload 29
  44. Image Upload 30
    Where is the E ring?
    Image Upload 31
  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. Image Upload 32
    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. Image Upload 33
     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. Image Upload 34
     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. Image Upload 35
    When the B/C ring fusion is cis, what will the C/D ring fusion be?
    • Trans
    • Co-planar
  51. What is a morphinan?
    • Image Upload 36
    • Opioids that have four rings
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    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.
    • Image Upload 38
    • 4-phenylpiperidine
  57. Image Upload 39
     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. Image Upload 40
     Can the phenyl ring change conformation in all multicyclic opioids?
    No
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    What is the orientation of the phenyl ring relative to the piperidine ring (D ring) in all multicyclic opioids?
    Axial
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     Is the phenyl ring essential?
    Yes
  61. Image Upload 43
    What part of the receptor does the phenyl ring bind to in all multicyclic opioids?
    TRP – one of the Van der Waals sites
Author
kyleannkelsey
ID
269310
Card Set
Opioids SAR 1
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Opioids SAR 1
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