Opioid SAR 2

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Author:
kyleannkelsey
ID:
269311
Filename:
Opioid SAR 2
Updated:
2014-04-05 13:58:17
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Opioid SAR
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Opioid SAR 2
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Opioid SAR 2
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  1. In the axial position, the phenyl ring will bind to which Van der Waals site in all multicyclic opioids?
    • 1
    • (site that normally binds the TYR residue of the enkephalins)

  2. Can the phenyl ring be equatorial in multicyclic opioids?
    • No
    • Only in Flexible opioids

  3. Under what conditions can the phenyl ring be equatorial?
    Only in Flexible opioids

  4. In the equitorial position, the phenyl ring will bind to which Van der Waals site in all multicyclic opioids?
    • 2
    • (site that normally binds the PHE residue of the enkephalins)

  5. What is this structure called?
    • Benzazocine
    • (Tricyclic ring)

  6. What is this structure called?
    • Morphinan
    • (Tetracyclic ring)

  7. Is this structure essential?
    Yes

  8. Which substituent determines the opioid receptor activity profile of the drug?


    The R1 substituent

  9. 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?
    • R1

  10. A CH3 at R1 will give the structure what characteristics?
    • Agonist action
    • Highly selective mu agonism

  11. A CH3 at R1 will bind to the receptor through what type of interaction?
    Hydrophobic interactions

  12. 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. 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. 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. What is this group?
    Allyl

  17. What is this group?
    Cyclopropylmethyl

  18. What type of action will this structure provide at the R1 site (N site)?
    Potent opioid antagonism

  19. What type of action will this structure provide at the R1 site (N site)?
    Potent opioid antagonism at the mu receptor

  20. 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. 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. 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. What structures at R1 (N site) will provide pure opioid antagonism/no analgesia at any receptor type at any dose?
    • N-allyl and N-cyclopropylmethyl

  24. Do N-allyl and N-cyclopropylmethyl at the R1 site provide pure opioid antagonism alone?


    • 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?


    • 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.  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. 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. What is this structure?
    Cyclobutylmethyl

  29. 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. A compound with a cyclobutylmethyl group at R1, will be used clinically for what?
    Kappa agonist action as an Analgesic

  31. Will a compound with a cyclobutylmethyl group at R1 be used for its mu antagonism?
    No, better options

  32. 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. Which one of these groups at R1 will provide pure mu opioid antagonism?
    Only the cyclopropylmethyl

  34. Under what conditions would you see pure opioid antagonism at the mu antagonists site with this group at R1?
    Never

  35. 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

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