6

1) Answer the following questions:

1A

Generic:

Nalorphine

Naloxone

Action:

Agonist antagonist

Pure antagonist

Why does each drug act like this?

- If N-Methyl substituent size is 3-5 (especially with unstauration or small carbocyclic
ring)
Antagonist at some or all receptors
Nalorphine
Agonist at one receptor &
Antagonist at another.
- 14-OH gp sterically forces the substituent to remain equatorial.

Naloxone
Pure antagonists at all receptors.
Mention the use of drug (B).
Naloxone: (Short-acting)

Used to reverse coma and respiratory depression of Opioid overdoses.
2A

Generic:
Action:

Codiene

Dextromethorphan

Opioids Used as Antitussives

What are the common str. similarities for both to act as antitussives?
3-O-CH3 derivatives of morphine and Levorphanol respectively.

Potent antitussive agents.
What are the proposed MOA for both?
Centrally acting
Decreasing the sensitivity of CNS cough centers to peripheral stimuli.
Mention the proposed metabolism of one of them.
Codiene
Undergoes metabolic O-demethylation to morphine.

Set your goals high enough to inspire you and low enough to encourage you

7
3A

Generic:

6-Acetylmorphine

3,6-diacetylmorphine (Heroine)

Action:

Agonist (4X Morphine potency)

Agonist (2X Morphine potency)

Which one of them has better affinity for the receptor? Why?
6-Acetylmorphine has better affinity
Its phenolic gp is free and will interact immediately with the analgesic receptors.
Which of them is stronger in its action? Why?
3,6-diacetylmorphine (Heroine) is stronger in action

Low opioid receptor affinity.
BUT

lipophilic BBB penetration

Where the 3-acetyl gp is hydrolyzed by esterases to produce 6-Acetylmorphine.
6-Acetylmorphine

agonist activity > Morphine.
- "Euphoric rush": Rapid BBB penetration of Heroin and the conversion to a potent
agonist. This makes this cpd a popular abuse drug.

4A

Generic:
Action:

Fentanyl
Agonist (80X Morphine potency)

Mepiridine
Agonist (1/4X Morphine potency)

Which of them is stronger? Why?

Fentanyl is stronger
No phenolic gp, but very lipophilic + rapid onset/short duration.
Mention the specific use for both drugs.
- Fentanyl
80X Morphine potency.
Used with nitrous Oxide for balanced anesthesia.

Fentanyl patch is used for severe chronic pain (provides analgesia for 72 hours).
- Meperidine
1/4X Morphine potency.

Used in child birth because of its rapid onset/short duration / No respiratory depression.
Enumerate a better alternative for drug (A). Sufentanil - Alfentanil.

8
5A

Generic:

Buprenorphine

Methadone

Action:

Potent partial agonist

Agonist

Which of them is stronger?

Buprenorphine
Mention the stereochemistry aspects of both indicating their uses.
Buprenorphine
An extra ring is added to make the molecule more rigid. Oripavines are very hydrophobic.
Rigidification
Limits the number of conformations that the molecule can adopt.

Retain the active conformation for the desired target.

Activity Selectivity Side effects.

Used in Opiod addict ttt program
Safe, no tolerance and blocks Heroin doses.
Methadone

Has a single asymmetric center (Marketed as a racemic mixture but the (-) isomer
possesses almost all the analgesic activity).

Used in opioid addict weaning programs (orally active with long duration of action).
6A

Generic:

Diphenoxylate

Hydrocodone

Action:

Antidiarrheal

Antitussive

Why does drug (A) co-administrated with Atropine?

Atropine
Block Ach "Anticholinergic: Abuse potential.
Which is stronger, Drug (B) or Codeine?
Hydrocodone is stronger than Codeine
Mention the metabolism of drug (A) indicating its activity.
Difenoxin: 5X more potent than Diphenoxylate ( CNS penetration - abuse potential).
Set your goals high enough to inspire you and low enough to encourage you

9
Complete the following statements:
1- Have Morphine-like structure.
2- Morphine-like pharmacological action - Naloxone.
3- Endorphines.
4- H-bond - Lipophilic - Anionic - Additional lipophilc.
5- Equatorially - Axially.
6- - Levo.
7- A ring - Basic Nitrogen - Phenolic OH (if the str. is rigid).
8- NSAIDs+ Weak oral opioid.
9- Severe acute pain.
10- Meperidine - Short duration and fast onset + No respiratory depression.
11- Heroin.
12- Naloxone.
13- Buprenorphine-Naltrexone.
14- Decrease - Decrease.
15- Esterases - Difenoxin.
16- Decrease the Abuse potential.
17- Decrease sensitivity of CNS cough centers - Decrease mucosal secretion.
18- Inactive.
19- Antagonist, if OH is present also, or mixed agonist antagonist.
20- Agonist.
21- 14-OH.
22- Weak - O-demethylation.
23- 6-Acetylmorphine - Euphoric rush.
24- Morphinans.
25- Not essential.
26- Oral - Long.
27- 4-Phenylpepridines - phenolic OH.
28- Meperidine - Fast - Short - Child birth.
29- 80X.
30- Sufentanil - Alfentanil.

Set your goals high enough to inspire you and low enough to encourage you

10
3) Modify the following structures as required:
Strusture
1-

Modify to
Full Antagonist

Write your answer here

Naltrexone

2-

Its metabolite

Difenoxin

3-

Antitussive

Dextromethorphan

Set your goals high enough to inspire you and low enough to encourage you