Medicinal Chemistry of Opioid Analgesics 2; SAR of Double Bond at C7-8, The N-Methyl Group, Common Metabolic Reactions

Question 1

What happens to analgesic activity upon hydrogenation (reduction) of the carbon 7-8 double bond? What does this give?

Answer 1

• Dihydromorphine

- Activity not compromised; double bond inessential

Question 2

What happens to analgesic activity when the N-Methyl group is oxidised/methylated to quaternary salts?

Answer 2

• No analgesic activity; inactive in vivo

- Quaternary salts with permanent cation (covalently bonded O/CH3) means no crossing of BBB to CNS receptors = inactive

Question 3

But when the N-oxide/methyl quaternary salts are injected into the CNS they show similar activity as morphine; what does this show?

Answer 3

• 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

Question 4

What is normorphine and its analgesic activity relative to morphine?

Answer 4

• Morphine w/the methyl group removed (from N)

- Has 25% activity of morphine

Question 5

Why does normorphine only have 25% the activity of morphine and what does this show about the importance of the methyl group?

Answer 5

• 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

Question 6

What happens to analgesic activity when the N is removed from morphine?

Answer 6

No activity at all; N is essential for activity/interacting with the receptor ionically (stronger than H-bonding/vDw)

Question 7

What happens to activity when the aromatic (A ring) ring is removed from morphine?

Answer 7

• Loss of activity; essential for analgesia

- Exhibits (important) vDw interactions in the binding pocket with aromatic AA side chains lining the active site

Question 8

How many chiral centres does morphine have?

Answer 8

5.

Question 9

What is the analgesic activity of morphine’s enantiomer; is there any receptor interaction?

Answer 9

None; inactive, ‘swivelled’ T-shape yields to only one receptor reaction (vDw at aromatic ‘A’ ring)

Question 10

What is epimerisation?

Answer 10

A change in structure at one stereochemical centre from the parent molecule when more than one chiral centre is present in the OG.

Question 11

What are the 3 receptor interactions that morphine undergoes?

Answer 11

• 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

Question 12

What is a pharmacophore?

Answer 12

The 3D positioning of the key functional groups with respect to each other.

Question 13

How can the pharmacophore be demonstrated?

Answer 13

• Skeletal pharmacophore

- Pharmacophoric triangles; corners show key functional groups OR demonstrate binding

Question 14

What are Phase I reactions?

Answer 14

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)

Question 15

What phase I reaction occurs to morphine? What enzyme is responsible?

Answer 15

• N-demethylation to give Normorphine (25% activity)
• Via CYP3A4
• Removal of methyl group for a H on N

Question 16

What phase I reactions occurs to codeine/what enzyme is responsible?

Answer 16

• 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

Question 17

What is Norcodeine? What phase I reaction occurs?

Answer 17

• 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

Question 18

Why are nor-metabolites (e.g. Normorphine/Norcodeine) of limited clinical relevance?

Answer 18

• Decrease in lipophilicity (distribution enhancing)

- Decreased hydrophobic activity at the receptor

Question 19

What is meant when a patient is described as a ‘poor metaboliser’?

Answer 19

Patient deficient in DYP2D6; unable to undergo O-dealkylation thus show little or no response to codeine-based analgesics.

Question 20

What Phase II metabolism do phenols undergo and how does it affect the drug?

Answer 20

• Glucuronidation/sulfation
• Increases hydrophilicity thus likelihood of excretion renally into urine (both conjugates found in urine of patients taking multicyclic opioids)

Question 21

Where are the Phase II enzymes UGT2B7/PAPS found?

Answer 21

In the liver and the GIT epithelium (intestinal transferases)

Question 22

How is morphine-3-glucorinide/sulfate produced?

Is it active?

Answer 22

• Phase II metabolism via UGT2B7 or PAPS

- Inactive; conjugate on phenolic -OH ‘3 position

Question 23

How is morphine-6-glucorinide produced?

Is it active?

Answer 23

• 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

Question 24

If morphine-6-glucuronide is more effective than morphine why isn’t it used?

Answer 24

• COST
• Morphine-6-glucorinide is metabolite generated by the body to rid of morphine; this conjugate is more readily excreted than morphine OG is

Question 25

What is the risk of morphine-6-glucuronide use and the elderly/renally impaired?

Answer 25

Though readily excreted normally, it can accumulate in said patients due to decrease in efficiency of metabolising enzyme = risk of inadvertent overdose.