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What groups at the R1 site provide mu agonism?
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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
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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)
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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
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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)
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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
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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)
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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)
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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.
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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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- 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
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If the C6 alpha-OH is oxidized to a ketone activity depends dramatically on what?
- 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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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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Which is more potent the Alpha series Benzazocine or Beta series?
Beta
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Do morphinans have similar binding modes to tetracyclic opioids?
No
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Do benzazocines have similar binding modes to tetracyclic opioids?
No
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Do morphinans have similar binding modes to benzazocines?
Yes
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