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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)
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Can the phenyl ring be equatorial in multicyclic opioids?
- No
- Only in Flexible opioids
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Under what conditions can the phenyl ring be equatorial?
Only in Flexible opioids
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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)
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What is this structure called?
- Benzazocine
- (Tricyclic ring)
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What is this structure called?
- Morphinan
- (Tetracyclic ring)
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Is this structure essential?
Yes
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Which substituent determines the opioid receptor activity profile of the drug?
The R1 substituent
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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
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A CH3 at R1 will give the structure what characteristics?
- Agonist action
- Highly selective mu agonism
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A CH3 at R1 will bind to the receptor through what type of interaction?
Hydrophobic interactions
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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)
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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
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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)
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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
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What is this group?
Allyl
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What is this group?
Cyclopropylmethyl
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What type of action will this structure provide at the R1 site (N site)?
Potent opioid antagonism
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What type of action will this structure provide at the R1 site (N site)?
Potent opioid antagonism at the mu receptor
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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)
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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
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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
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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
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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
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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
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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
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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
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What is this structure?
Cyclobutylmethyl
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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
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A compound with a cyclobutylmethyl group at R1, will be used clinically for what?
Kappa agonist action as an Analgesic
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Will a compound with a cyclobutylmethyl group at R1 be used for its mu antagonism?
No, better options
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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
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Which one of these groups at R1 will provide pure mu opioid antagonism?
Only the cyclopropylmethyl
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Under what conditions would you see pure opioid antagonism at the mu antagonists site with this group at R1?
Never
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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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