The Medicinal Chemistry of Opioid Analgesics 4

Question 1

What happens to the analgesic properties of morphine upon the removal of ring B, C and D

Answer 1

4-phenylpiperidines

(ethyl bridge and the aromatic ring only original features

Question 2

What class of drug is pethidine? 
What properties does it possess?

Answer 2

4-phenylpiperidines 20% action of morphine
Rapid onset of action but short duration
+good for child birth, less likely to cause respiratory depression

Question 3

Are there any popular/successful piperidine derivatives?

Answer 3

Fentanyl, 100 times more potent than morphine
Added acetylated N group
Contains two Ns and an acetyl group

Question 4

What are the properties of fentanyl?

Answer 4

More potent than morphine

Lacks a phenolic -OH but extremely lipophillic

Question 5

What analgesic properties does a molecule have if ring B, C, D and E are removed?

Answer 5

Methadone
has a straight chain and a single asymmentric centre
still posses ring A containing an alcoholic -OH

Question 6

What are the two enantiomers of methadone and their properties?

Answer 6

R 2x more potent than morphine

S inactive

Question 7

What are the properties of methadone?

Answer 7

Less severe emesis, constipation, sedation, euphoria and withdrawal symptoms
Used to wean off addicts from opiate use

Question 8

What is unusual about ,methadone compared to other opioid analgesics?

Answer 8

Only one of three marketed that do not contain the piperidine ring

Question 9

What do the two enantiomers of methadone contribute to? It is given in a racemic mixture

Answer 9

R(-) isomer is analgesic activity
S(+) isomer antagonises the NMDA (responsible for the electrical signalling between brain and spinal cord) SPINE–>BRAIN at central terminal of dorsal root ganglion

Question 10

What serious side effects can be caused by the S (+) enantiomer of methadone?

Answer 10

Antagonism of the NMDA receptor can cause prolonged QT interval prolonged
Torsades de pointes (twisting the points on ECG), arrythmias on ECG

Question 11

How does methadone have prolonged onset of action?

Answer 11

Generates several active N-dealkylated and C3 reduced metabolites with a longer half life

Question 12

Serious interactions between methadone and which kind of drugs can cause heart arrythmias and respiratory toxicity?

Answer 12

Interactions with drugs that induce or inhibit (competitors) of the CYP enzymes

Question 13

Explain methadone administration via “swish and spit”

Answer 13

Pretreated solution of methadone with an alkalising agent increases the pH of the saliva from 6.4 to 8.5
(the environment is now basic and the methadone is in an unionised state), can be absorbed
85% can be absorbed in 2.5 minutes of buccal absorption

Question 14

How does tramadol work to produce analgesic effect?

Answer 14

Weak μ agonist but with multiple mechanisms of action

-30% of analgesic effect blocked by naloxone

Question 15

At recommended doses what is a benefit of tramadol?

Answer 15

Minimal effects on respiratory rate, heart rate, blood pressure and GI transit times

Question 16

Patients allergic to codeine should not receive tramadol, why?

Answer 16

Similarity in structure (codeine has methylated phenolic -OH) -> only ether O in ring D and -OH in ring D missing
Increased risk of anaphylactic shock

Question 17

What happens when tramadol is metabolised?

Answer 17

CYP2D6 N demethylation makes a more potent opioid receptor agonist

Question 18

Is tramadol a racemic mixture?

Answer 18

Of the cis-isomers
IR, 2R enantiomer is 30 times more potent that IS, 2S enantiomer but the racemic formulation displays improved tolerability

Question 19

What is the cause of most unwanted side effects and how can this be overcome?

Answer 19

Structural flexibility and the promiscuous nature of ligands causes them
Conformational restrictions make ligand more specific and reduce chances of side effects

Question 20

What is the significance of thebaine?

Answer 20

Precursor molecule with a diene in ring C
This lends itself to modification via the Diels-Alder reaction
Oxycodone precursor molecule

Question 21

Properties of oxycodone and structure?

Answer 21

Added -OH to ring B/D carbon
O-CH3 at carbon 3
65%-85% bioavailability
Not a prodrug, correlation between analgesia and oxycodone plasma conc

Question 22

What is the Diels-Alder reaction?

Answer 22

Reaction between a diene and a dieneophile to form a six membered ring containing a double bond
This produces oripavines

Question 23

What is the Grignard reaction and its uses?

Answer 23

Drug extension by 1,2 extension method

Adding groups to oripavines has lead to important compounds created

Question 24

What is etorphine and where is it derived from?

Answer 24

Dervied from thebaine (from the diene containing thebaine via Diels-Alder), added group via extension (by the Grignard reaction)

Highly lipophillic and 10000 times more potent than morphine
Used as a tranquiliser for large animals e.g. elephants

Question 25

Aside from etorphine, what other molecule is derived from oripavine drug extension?

Answer 25

Buprenorphine - good analgesic activity and low risk of addiction
Formulated as a sublingual tablet

Question 26

Which drugs have a six membered ring with a carbon double bond?

Answer 26

Etorphine and buprenorphine = opivarines

Derived from thebaine