Flashcards in The Medicinal Chemistry of Opioid Analgesics 2 Deck (19)
What is the result of hydrogenation of morphine and what conditions are needed?
The removal of the double bond between carbon 7 and 8
Palladium catalyst on charcoal
What is the effect on the analgesic action of morphine when the double bond between carbon 7 and 8 is removed?
Analgesia not affected / activity not compromised therefore double bond not essential
What modifications can be made to the tertiary amine group?
O- can be added onto the N-amine group, making it an N-oxide
A methyl group can be added to the N-amine group, making it an N-methyl
What does N-methyl and N-oxide formation do to the analgesic properties of morphine?
The molecules are now charged and therefore cannot cross the BBB
How can the charged problems with N-methyl and N-oxide be overcome?
If injected directly into the CNS, then possess similar analgesic activity as morphine
What is the structure of Normorphine like?
N-methyl group is removed from the parent structure so -NH is the functional group
25% the activity of morphine
Less basic / more polar structure
What happens if the nitrogen atom is removed from the morphine structure
Total abolition of activity as cannot bind to aspartic acid residue in the binding site
What happens to the analgesic activity of morphine upon the removal of ring A (aromatic)?
Essential ring, without it the activity of morphine is lost
What happen to the analgesic activity if the ether bridge is removed from the morphine structure?
Nothing, not required for activity just part of the scaffold
If all five chiral centres are inverted in the morphine structure how does this affect the analgesic properties of the morphine molecule?
Completely inactive as the T shape is configured in a different arrangement i.e. only the aromatic ring VDW forces are able to act
What is epimerisation?
In a structure with multiple chiral centres, only one is manipulated or changed to form am epimer
What are the three main ways that the morphine molecule binds to the active site of the receptor?
-OH as a hydrogen bond donor acts at Histidine residue via water, helping to wick into the active site
van der Waals forces acting at the binding site from the aromatic ring
Ionic bonding between the amine conjugate acid form and aspartic acid
How is codeine metabolised (phase I metabolism)?
Codeine as a prodrug - important CYP2D6 O-demethylation to morphine for analgesic effect
N-demethylation CYP3A4 to norcodeine can be further metabolised to normorphine by O-demethylation
Codeine is effective to varying degrees in individuals, why?
Patients deficient in CYP2D6 are deficient in the metabolising enzyme needed for O-demethylation to convert codeine to morphine. Without this step morphine is not derived and so no analgesic effect is felt
What are the phase II metabolism pathways for morphine?
UGT2B7 or PAPS are the enzymes needed for glucuronidation (and/or sulphation) of morphine
What products are derived from glucuronidation of morphine (phase II metabolism)?
Morphine-6-glucuronide (active, much more potent than morphine)
How can conjugation impact on oral bioavailability?
Conjugation in the GI tract can cause reduced F
How do phenols conjugate?
Can conjugate with glucuronic acid or with sulfate
-both conjugates found in the urine of patients taking multicyclic opioids