Opioid SAR 2

Home > Preview

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


  1. Image Upload
    In the axial position, the phenyl ring will bind to which Van der Waals site in all multicyclic opioids?
    • Image Upload
    • 1
    • (site that normally binds the TYR residue of the enkephalins)
  2. Image Upload
    Can the phenyl ring be equatorial in multicyclic opioids?
    • No
    • Only in Flexible opioids
  3. Image Upload
    Under what conditions can the phenyl ring be equatorial?
    Only in Flexible opioids
  4. Image Upload
    In the equitorial position, the phenyl ring will bind to which Van der Waals site in all multicyclic opioids?
    • Image Upload
    • 2
    • (site that normally binds the PHE residue of the enkephalins)
  5. Image Upload
    What is this structure called?
    • Benzazocine
    • (Tricyclic ring)
  6. Image Upload
    What is this structure called?
    • Morphinan
    • (Tetracyclic ring)
  7. Image Upload
    Is this structure essential?
    Yes
  8. Image Upload
    Which substituent determines the opioid receptor activity profile of the drug?
    Image Upload

    The R1 substituent
  9. Image Upload
    Where would you look on the opioid structure to determine if it will act as a mu agonist, kappa agonist/mu antagonist, or a pure opioid antagonist?
    • Image Upload
    • R1
  10. Image Upload
    A CH3 at R1 will give the structure what characteristics?
    • Agonist action
    • Highly selective mu agonism
  11. Image Upload
    A CH3 at R1 will bind to the receptor through what type of interaction?
    Hydrophobic interactions
  12. Image Upload
    An H at R1 will give the structure what characteristics?
    • Agonist action
    • Highly selective mu agonist
    • Poor analgesic activity compared to alkylated versions
    • (Also called the Nor-metabolite)
  13. Why will An H at R1 will give the structure decreased analgesic activity?
    • 1) Loss of the hydrophobic interaction at the mu agonist site
    • 2) Decreased ability to penetrate the BBB
  14. Image Upload
    An Aralkyl (e.g., -CH2-CH2-Ar) at R1 will give the structure what characteristics?
    • Agonist action
    • Selective mu agonist
    • Compared to N-methyl opioids = will have a higher affinity for the mu receptor agonist site
    • Stronger hydrophobic forces (more carbons to bind)
    • Stronger Van der Waals bonds (presence of the aromatic ring)
    • Greater lipophilicty/CNS distribution (higher log P)
  15. Image Upload
    A N-phenylethyl-substituted multicyclic opioid (aralkyl) at R1 will provide what level of potency to this structure?
    • 10x higher potency than a normal N-CH3
    • Because of its higher mu affinity and faster CNS distribution
  16. Image Upload
    What is this group?
    Allyl
  17. Image Upload
    What is this group?
    Cyclopropylmethyl
  18. Image Upload
    What type of action will this structure provide at the R1 site (N site)?
    Potent opioid antagonism
  19. Image Upload
    What type of action will this structure provide at the R1 site (N site)?
    Potent opioid antagonism at the mu receptor
  20. Image Upload
    What aspects of these R1 substituents allow them to bind the Antagonist site of the mu receptor?
    • 3 carbon length
    • Partial negative (high e- density)
  21. Image Upload
    What partial charge do these groups have and why?
    • Partial negative (high e- density)
    • Due to:
    • pi electron in the double bond in the Allyl
    • Very highly strained ring that clusters the sp3 orbitals in the Cyclopropylmethyl
  22. Image Upload
    The partial negative charge on these two groups allows them to bind to what residues in the mu antagonist site and by what interactions?
    • MET and TYR
    • By dipole-dipole interactions
  23. Image Upload
    What structures at R1 (N site) will provide pure opioid antagonism/no analgesia at any receptor type at any dose?
    • Image Upload
    • N-allyl and N-cyclopropylmethyl
  24. Image Upload
    Do N-allyl and N-cyclopropylmethyl at the R1 site provide pure opioid antagonism alone?
    Image Upload

    • No
    • Require:
    • Pentacyclic ring system
    • 7,8-dihydro-6-one substituted C ring
    • 14 -OH
    • B/C configuration must be cis
  25. What are the structural requirements for pure opioid antagonism?
    Image Upload

    • Pentacyclic ring system
    • 7,8-dihydro-6-one substituted C ring
    • 14 -OH
    • B/C configuration must be cis
    • Aided with N-allyl and N-cyclopropylmethyl or N-cyclobutyl
  26. Image Upload
     If a structure does not have all the necessary requirements for mu antagonism (shown), but has an N-allyl or N-cyclopropylmethyl group, what kind of action would you expect?
    • Potent mu antagonism in lower doses
    • Kappa agonism with analgesia and significant dysphoria at higher doses
    • Strong dysphoria makes them almost useless as analgetics
    • Used to reverse opioid overdose
  27. Image Upload
    What is the main use of multicyclic opioids with an N-allyl or N-cyclopropylmethyl
    Used as antagonists to reverse opioid overdose or maintain a drug-free state in addiction recovery
  28. Image Upload
    What is this structure?
    Cyclobutylmethyl
  29. Image Upload
    The cyclobutylmethyl group at R1 always provides what type of activity?
    • Potent kappa agonism and strong mu antagonism
    • May have some low-efficacy partial  agonism
  30. Image Upload
    A compound with a cyclobutylmethyl group at R1, will be used clinically for what?
    Kappa agonist action as an Analgesic
  31. Image Upload
    Will a compound with a cyclobutylmethyl group at R1 be used for its mu antagonism?
    No, better options
  32. Image Upload
    How do these two groups compare as R1 substituents?
    • Cyclobutyl will have weaker antagonism than Cyclopropyl
    • Cyclobutyl ring has less ring strain =less negative character/electron density
    • Cyclobutyl is slightly longer = doesn’t fit as well as 3 carbon N-allyl and cyclopropylmethyls into the mu antagonist site
  33. Image Upload
    Which one of these groups at R1 will provide pure mu opioid antagonism?
    Only the cyclopropylmethyl
  34. Image Upload
    Under what conditions would you see pure opioid antagonism at the mu antagonists site with this group at R1?
    Never
  35. Image Upload
    How do these two groups compare as R1 substituents?
    • Cyclobutyl will have weaker antagonism than Allyl
    • Cyclobutyl ring has less negative character/electron density than the double bond
    • Cyclobutyl is slightly longer = doesn’t fit as well as 3 carbon N-allyl into the mu antagonist site

Card Set Information

Author:
kyleannkelsey
ID:
269311
Filename:
Opioid SAR 2
Updated:
2014-04-05 17:58:17
Tags:
Opioid SAR
Folders:
Opioid SAR 2
Description:
Opioid SAR 2
Show Answers:

Home > Flashcards > Print Preview