Stephen Husbands - The Opioids Flashcards
Pharmacological effects of Morphine are produced by the…
Alkaloids
Morphine is ____ due to it’s tertiary amino group
BASIC
The N-methyl group of Morphine can convert between the ___ and ___ positions
Axial and Equatorial
In order to see what functional groups were important for analgesia, chemists can create different ______
Analogues
Modifying or removing the 6 hydroxy group of Morphine does what to analgesic properties?
Doesn’t affect analgesia
Activity of Morphine is dependant on what 3 points?
- Phenol ring
- Aromatic ring
- Tertiary amine
What happens to the tertiary amine of morphine when it interacts with it’s target site?
- It is protonated and ionised - forms ionic bonds
What interaction does the phenol of Morphine have with the target site?
- Hydrogen bonding
What interaction does the aromatic group of Morphine have with the target site?
- VDW forces
What bonding does the tertiary amine of Morphine have with the target site?
- Ionic bonding - through protonated and ionised nitrogen
What are the 3 main types of opioid receptor?
Kappa, Mu and Delta
Activation of which receptor results in the strongest analgesic effects?
Mu
Which receptor results in the strongest and most dangerous side effects? They are…
Mu
- Resp depress
- Addiction
- Euphoria
What does pharmacodynamics refer to?
- Ability of drug to bind to it’s target and produce pharmacological effect
The phenol acts as a hydrogen bond…
Donor - forms bond with hydrogen bond acceptor in target site
The aromatic ring of morphine can form _____ forces with hydro____ sites in the binding site
VDW forces with hydrophobic sites in the binding site
Pharmacokinetics refers to…
Ability of drug molecule to reach target and survive in the body
Morphine is relatively… polar or non polar?
POLAR
The amine group of morphine is a ____ base so morphine can exist in the free base and ionised form. What does this mean in relation to crossing the BBB?
- It is a WEAK base
- This means unionised form of Morphine can cross the BBB whereas the ionised form of Morphine cannot
Once the free base of Morphine has crossed the BBB it must ____ in order to interact with the target binding site
IONISE
If the 6 Hydroxy group of Morphine is altered then the pharmaco____ of the molecule will change…
PharmacoKINETICS
Give an example of how changing the 6 hydroxy group of morphine will change it’s pharmaco______
If the 6 hydroxy group of Morphine is made more NON polar e.g making it an acetyl group (6-acetylmorphine) then it is more able to cross the BBB and be absorbed due to it’s high lipophilicity, increasing it’s potency
Heroin differs from Morphine in what way?
- The phenol has been acetylated
- The 6-hydroxy group have been acetylated
- It is more potent than morphine
- The 3-acetyl group requires hydrolysis before it can interact with the receptor via H bonding (phenol group)
Codeine undergoes what type of metabolism to form what?
O-demethylation to form Morphine
Medicinal chemists tried altering the N-methyl group of Morphine and found what?
- Increasing the size of the change by adding a butyl group decreased activity
- Increasing the size of the change past butyl increased activity slightly again
- Adding a lipophilic phenethyl ring dramatically increased activity!
What did the addition of a lipophilic ring to the N-methyl group of Morphine suggest?
- That a hydrophobic binding region is present in the binding site
Nalorphine has an allyl group off the Nitrogen - what does this mean?
- It is an antagonist at the Mu receptor
- It is a weak agonist at the Kappa receptor
Removing the ring with the 6-hydroxy group results in the formation of…
Benzomorphans
Benzomorphans ____ analgesic activity
retain
List some different clinical difference between morphine and methadone
Methadone:
- Less severe side effects
- Less emetic effects
- Less sedation
- Less euphoria
Methadone is a __phenyl____amine
Diphenylpropylamine
Explain the test that was conducted with Naloxone to test for stereospecific binding…
- Naloxone radiolabelled
- Measured binding under 2 conditions
1) XS non radiolabelled naloxone
2) XS non radiolabelled naloxone enantiomer
Less binding in condition 1
More binding in condition 2 - as enantiomer doesn’t specifically bind receptor - diff stereochemistry
STEREOSPECIFIC BINDING PROVED
Morphine and enkephalins have WHAT in common?
Tyrosine skeleton (phenol attached to the ring through to the tertiary amine) - both interact with the same aspartic acid residue in the receptor site
The MESSAGE part of a molecule is responsible for what?
Pharmacological activity
The ADDRESS part of a molecule is responsible for what?
Target selectivity
Kappa specificity is due to WHAT?
- A basic nitrogen on the address part of the molecule
The presence of WHAT can make a nitrogen unable to protonate and therefore reduce kappa specificity and potency of the compound?
An oxygen - amide group.
As electrons interact with the carbonyl
Antagonism is due to presence of what?
- Cyclopropyl group off nitrogen on message
- Cyclobutyl group off nitrogen on message
- Allyl group off nitrogen on message (double bond)
Delta specificity is due to what?
- Aromatic ring presence on address
Mu specificity is due to what?
- Presence of double bond oxygen group off aromatic ring
What are the 4 strategies in developing Morphine analogues?
- variation of substituents (aromatic, nitrogen, 3-OH)
- drug extension (adding chains to nitrogen to see if further binding sites present between analogue and receptor e.g hydrophobic region?)
- simplification - remove rings of skeleton to see if needed or not for pharmacological effect
- rigidification - add extra ring to increase rigidity - diels-alder adduct - Addition of ketone group and undertaking Grignard reaction adds acetylates 6-OH group and the ketone inc lipophilicity and inc potency
All analogues with the phenylpiperidine ring in the equatorial configuration are… ASK ???
antagonists - independent of the R group
