E. The medicinal chemistry of opioid analgesics 2 Flashcards
Is the double bond on the C ring important in the analgesic activity of morphine ?
Non it is not essential for biological activity when removed.
How is the double bond in the morphine C ring removed?
Hydrogenation, removal of double bind which is a reduction process as we are adding hydrogen.
Does N-oxide and N-Methyl posses any biological activity in vivo?
NO, this is because they’re permanently charged molecule therefore cannot cross the BBB. Only neural compounds can cross the BBB. This means that it cannot act on the receptors in the brain cells.
What would happen to the biological activity if N-oxide and N-methyl was injected into the CNS? What can this tell us about the charged form of the molecule acting on the receptor?
It is biologically active and has similar analgesic affect to morphine.
The charged form is essential for biological activity at the receptor.
What molecule is made when we remove the methyl group from morphine ?
Normorphine
What happens to the biological activity of morphine when the methyl group is removed to create normorphine?
The biological activity slightly decreases however it is not essential. The molecule becomes more polar therefore is less likely to cross the BBB
What happens to the biological activity when a nitrogen atom (praparadile) is removed from from morphine ?
There is no biological activity at all. This is because once it crosses the BBB, the molecule has no ability to be protonated. Protonation, leading to the positively charged conjugate acid from the basic amine is essential for it to interact with the receptors. Nitrogen needs to be in the ionised form but still needs to gain access to the brain tissue.
What happens if you remove the aromatic A ring ?
There will be a loss in analgesic activity
What happens when you remove the ether bridge on the D ring ?
No activity will be lost
What can’t nitrogen form chiral centres ?
Can rapidly interconvert at ambient temperatures
What happens when you convert morphine into its enantiomer ?
There is no biological activity, as it cannot bind to the opioid receptor. All groups are swapped around. Aromatic ring can no longer bind
What is epimerisation ?
One of two molecules that differ in the spatial arrangement of atoms or groups surrounding only one of two or more chiral atoms in the structure
What happens to the biological activity of morphine when it undergoes epimerisation?
The activity is reduced to 10%. This is because it results in poor conformation form receptor binding
What interactions does the phenolic -OH group possess?
H-bonding (donates hydrogen bond)
Interacts with histidine
What interactions does the aromatic ring possess?
Van der waals interaction
