Medicinal Chemistry of Opioid Analgesics 2; SAR of Double Bond at C7-8, The N-Methyl Group, Common Metabolic Reactions Flashcards
What happens to analgesic activity upon hydrogenation (reduction) of the carbon 7-8 double bond? What does this give?
- Dihydromorphine
- Activity not compromised; double bond inessential
What happens to analgesic activity when the N-Methyl group is oxidised/methylated to quaternary salts?
- No analgesic activity; inactive in vivo
- Quaternary salts with permanent cation (covalently bonded O/CH3) means no crossing of BBB to CNS receptors = inactive
But when the N-oxide/methyl quaternary salts are injected into the CNS they show similar activity as morphine; what does this show?
- That a protonated, positive, charged N is essential for interaction w/receptor (ionic bonding w/aspartic acid residue)
- Protonation of weakly basic N essential for activity
What is normorphine and its analgesic activity relative to morphine?
- Morphine w/the methyl group removed (from N)
- Has 25% activity of morphine
Why does normorphine only have 25% the activity of morphine and what does this show about the importance of the methyl group?
- Removal of methyl group yields less basicity (less likely to be protonated once crossed BBB) and greater polarity (harder to cross BBB in the first place w/o lipophilic methyl group)
- Thus the N-methyl is not ‘essential’ but greatly helps lipophilicity
What happens to analgesic activity when the N is removed from morphine?
No activity at all; N is essential for activity/interacting with the receptor ionically (stronger than H-bonding/vDw)
What happens to activity when the aromatic (A ring) ring is removed from morphine?
- Loss of activity; essential for analgesia
- Exhibits (important) vDw interactions in the binding pocket with aromatic AA side chains lining the active site
How many chiral centres does morphine have?
5.
What is the analgesic activity of morphine’s enantiomer; is there any receptor interaction?
None; inactive, ‘swivelled’ T-shape yields to only one receptor reaction (vDw at aromatic ‘A’ ring)
What is epimerisation?
A change in structure at one stereochemical centre from the parent molecule when more than one chiral centre is present in the OG.
What are the 3 receptor interactions that morphine undergoes?
- H-bonding of phenolic OH of A ring with histidine residue (via a H2O that ‘wicks’ reaction)
- van der Waals of aromatic ‘A’ ring with aromatic AA side chains lining active site
- Ionic bonding of protonated amine (conjugate acid form) with aspartic acid residue at active site
What is a pharmacophore?
The 3D positioning of the key functional groups with respect to each other.
How can the pharmacophore be demonstrated?
- Skeletal pharmacophore
- Pharmacophoric triangles; corners show key functional groups OR demonstrate binding
What are Phase I reactions?
Body’s way of trying to create more hydrophilic species to accelerate elimination from the body e.g. cytochrome P450 oxidases, reduction, hydrolysis (for reactive/polar groups)
What phase I reaction occurs to morphine? What enzyme is responsible?
- N-demethylation to give Normorphine (25% activity)
- Via CYP3A4
- Removal of methyl group for a H on N
What phase I reactions occurs to codeine/what enzyme is responsible?
- N-demethylation to Norcodeine (inactive)
- Via CYP3A4
- Removal of methyl group for a H
- O-demethylation (to give phenolic -OH at ‘3) giving MORPHINE
- Via CYP2D6
- Methyl ether > phenolic -OH
What is Norcodeine? What phase I reaction occurs?
- Codeine (w/methyl instead of phenolic -OH) w/o a methyl on the N (inactive)
- O-demethylation (to give phenolic -OH at ‘3) to Normorphine
- Via CYP2D6
- Methyl ester > phenolic OH
Why are nor-metabolites (e.g. Normorphine/Norcodeine) of limited clinical relevance?
- Decrease in lipophilicity (distribution enhancing)
- Decreased hydrophobic activity at the receptor
What is meant when a patient is described as a ‘poor metaboliser’?
Patient deficient in DYP2D6; unable to undergo O-dealkylation thus show little or no response to codeine-based analgesics.
What Phase II metabolism do phenols undergo and how does it affect the drug?
- Glucuronidation/sulfation
- Increases hydrophilicity thus likelihood of excretion renally into urine (both conjugates found in urine of patients taking multicyclic opioids)
Where are the Phase II enzymes UGT2B7/PAPS found?
In the liver and the GIT epithelium (intestinal transferases)
How is morphine-3-glucorinide/sulfate produced?
Is it active?
- Phase II metabolism via UGT2B7 or PAPS
- Inactive; conjugate on phenolic -OH ‘3 position
How is morphine-6-glucorinide produced?
Is it active?
- Phase II metabolism via UGT2B7
- More active than morphine; phenolic ‘OH on ‘3 remains, glucuronic acid group conveys greater activity; higher affinity for μ-receptor
If morphine-6-glucuronide is more effective than morphine why isn’t it used?
- COST
- Morphine-6-glucorinide is metabolite generated by the body to rid of morphine; this conjugate is more readily excreted than morphine OG is
What is the risk of morphine-6-glucuronide use and the elderly/renally impaired?
Though readily excreted normally, it can accumulate in said patients due to decrease in efficiency of metabolising enzyme = risk of inadvertent overdose.
