Opioid SAR 3

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    What groups at the R1 site provide mu agonism?
    • H
    • CH3
    • Arylalkyl
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    What groups at the R1 site will provide mu antagonism?
    • “Antagonists 2”
    • Cyclobutylmethyl (parital antagonism)
    • Cyclopropylmethyl
    • Allyl
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    What substituents might we see at the R2 (C3) site?
    H or CH3
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    What substituent at R2 is required for multicyclic opioids at the mu receptor?
    H
  5. Why is H required for multicyclic opioids at the mu receptor?
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    • H donor for critical H-bond with HIS on mu receptor
    • Needed to bind to the Van der Waals 1 site ( replaces enkelphalin TYR-OH)
  7. Why is H not required for flexible opioids at the mu receptor?
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    • The Van der Waals 2 does not require an OH
    • PHE of enkephalin’s does not have an OH
  9. Do meperidine, fentanyl, and methadone require a phenolic OH for high mu receptor affinity?
    • No, they are flexible opioids
    • Bind the Vand Der Waals 2 site
    • They mimic the PHE on enkephalin which does not have an OH
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    What is the disadvantage of having a C3 phenolic OH group on an opioid?
    • Vulnerable to inactivating pre-hepatic (gut) and first pass Phase II metabolism
    • Compromised oral bioavailability = Premature conjugation with glucuronic acid or PAPS (sulfate)
    • In vitro oxidation to inactive quinine = require protection from light, base, and O2
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     What characteristic does CH3 group (methoxy ether) at R2 have?
    • Enhances CNS distribution
    • Destroys mu receptor affinity (no longer an H-donor to HIS)
    • Slows OOA
    • Incomplete activation/poor potency (10%)
    • 12x decrease in opioid activity
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     If you have a CH3 group (methoxy ether) at R2, will your compound be active?
    Not until CYP2D6 O-dealkylation occurs in the CNS
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    CYP2D6 O-dealkylation of an R2 methoxyether in the CNS has what disadvantages?
    • Slow
    • Incomplete (only about 10% is converted)
    • 12x decrease in opioid activity
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    How does the activity of these two compounds compare?
    The one on the Left (methoxy) has 12x lower activity than the one on the right (morphine)
  15. What group commonly has poor CYP2D6 metabolism?
    Asians
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    Which of these drugs might a person who is PM CYP2D6 not derive much benefit from?
    The one on the Left (methoxy) because it needs to be O-dealkylated in the CNS by CYP2D6
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    Is O-dealkylation of a R2 methoxyether (like codeine) required for antitussive action?
    No
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     What are the possible substituents at R3 (C14)?
    H or OH
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    What are the characteristics of an R3 (C14) OH compared to a Hydrogen?
    • B will have reduced lipophilicity = Decreased CNS distribution compared to B
    • B will have increased mu receptor affinity due to an efficient H-bond with TYR
    • B will have better N substituent conformation
    • B will have 2-3x stronger mu opioid action
    • A will have more antitussive action
  20. Which of these drugs could be used for its antitussive action?
    B
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    How do these drugs compare?
    • A has 14-20 fold increase in analgesic activity due to the carbon rich acid
    • A has significantly enhanced CNS distribution
    • A has significantly enhanced hydrophobic interactions at the mu receptor
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    What are the common group seen at R4?
    • OH (H-donor at mu)
    • keto (H-acceptor at mu)
  23. What type of opioids will have group at R4?
    • Pentacyclic opioids (derivatives of morphine)
    • All other multicyclic opioids will be unsubstituted at this position (R4=H)
  24. The effect of a 6-OH or 6-keto on  receptor affinity depends on both the C6 substituent and the nature of the 7,8 bond.
  25. The C6 alpha-OH group that we see in morphine and codeine acts as a H-_______ in a hydrogen bond with the mu receptor ASN residue.
    H-donor
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    What do we call a double bond present between carbons 7 and 8?
    7,8-dehydro C ring
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    7,8-dehydro C ring has what characteristics?
    • Very rigid ring
    • Holds the C ring in a pseudo-boat conformation
    • Positions the C6 alpha-hydroxy group towards the ASN H-accepting site
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    What is this 7-8 conformation called?
    7, 8 dihydro
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    7,8-dehydro C ring has what characteristics?
    • Flexible
    • Alpha OH is able to H- bond (donor) with the mu ASN
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     Compare these two drugs
    • Both are able to H-bond with the mu ASN
    • A is flexible
    • B is rigid and in the pseudo-boat conformation
    • Equal opioid activity (with C6 alpha-OH present)
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     The 6 alpha-OH group has what characteristics?
    • Responsible for the delayed allergic response to alkaloidal opioids
    • Causes release of histamine (intense itching and nausea) through activation of protein kinase A and inositol triphosphate kinase
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     Can the allergic reaction caused by the 6 alpha-OH be revered by a pure opioid antagonist?
    No
  33. If the C6 alpha-OH is oxidized to a ketone activity depends dramatically on what?
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    • Whether there is a 7,8 dihydro (flexible) or a 7,8-dehydro (rigid) C-ring
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    A keto group at C6 and 7,8-dehydro C ring would have what effect on activity?
    • pseudo-boat conformation would push the negative 6-keto oxygen into the mu negative ASN
    • They would repel each other
    • Activity decreases 3x
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    A keto group at C6 and 7,8-dihydro C ring would have what effect on activity?
    • The keto oxygen would be able to move and can interact with the ASN residue as a H-acceptor (ASN NH2 group acting as a H-donor)
    • Increases mu affinity 6-8x over the dehydro form
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    What effect does an H at C6 have on activity?
    • No hydrogen bonding with opioid receptors
    • Analgetic activity increases 10x compared to the 6alpha-OH derivative
    • Due to increased lipophilicity and CNS distribution
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    Morphines (pentacyclic compounds): The B/C cis isomers are _______ active than the B/C trans isomers.
    10 times more
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    Morphinans (tetracyclic compounds): The B/C trans isomers are __________ active than the B/C cis isomers.
    2 times more
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    Benzazocines (tricyclic compounds): If the CH3 at C11 is Alpha (dotted line), the hydrogen that is also at C11 will be _______.
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    • Beta
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    Is this an alpha series Benzazocine or Beta series?
    Alpha series (see C11 dotted line to CH3)
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    This conformation is relatable to what B/C ring fusion?
    Cis
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     This conformation is relatable to what B/C ring fusion?
    Trans
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    Benzazocines (tricyclic compounds): If the CH3 at C11 is Beta (solid line), the hydrogen that is also at C11 will be _______.
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    • Alpha
  44. Which is more potent the Alpha series Benzazocine or Beta series?
    Beta
  45. Do morphinans have similar binding modes to tetracyclic opioids?
    No
  46. Do benzazocines have similar binding modes to tetracyclic opioids?
    No
  47. Do morphinans have similar binding modes to benzazocines?
    Yes
Author
kyleannkelsey
ID
269332
Card Set
Opioid SAR 3
Description
Opioid SAR 3
Updated