Structure activity Relationship of Opiods

1. Structure Activity Relationship
of Opioids
Dr. Suji V. S.
Dept of Pharmacology.

2. Classification of opiods
based on structure
Eg.
Pentacyclic Morphines Codeine ,Buprenorphine,
Oxycodone, Diacetylmorphine
(Heroin)
Tetracyclic Morphinan Levorphanol, butorphanol
Tricyclic Benzazocine Pentazocine, Phenazocine
Bicyclic Phenylpiperidine Meperidine

3. SAR
Modification to Morphine

4. Chiral centers
• Morphine has 5 Chiral centers.
• Only the Levo(-) rotatory isomer is active

5. Biological action of opiods
• depends on
1. Phenolic hydroxyl group
2. 6 hydroxyl
3. Double bond between 7 & 8 c
4. N-methyl group
5. Ether (E) bridge
6. Aromatic ring

6. Phenolic hydroxyl group
• is needed for binding of μ & κ receptors;
• seen in all potent µ agonist.
• Changing -OH to just –H or -OCH3 lowers activity.
R= C3 substituent Activity effect
-H Decrease
-OH Morphine
-OCH3 (codeine) Decrease (1/3)

7. R= Nitrogen substituent Effect
3-5 Carbons
(with double bond/ small cyclic or
aromatic rings) eg. CH2CH=CH2
µ antagonist
>5c (in chain or ring ) µ agonist
Aralkyl
CH2CH2Ph
(Total 8 C)
µ agonist (10X
morphine)
N-methyl group
• Interacts hydrophobically with μ receptor.
• Size of substituent on Nitrogen dictates
potency and agonist/antagonist activity.

8. Opiod antagonists

9. 14 β H/OH moiety
• Addition of OH at 14 β position
1. Increases activity (2-3X)
2. Increases penetration of BBB
3. Decrease in antitussive action

10. 7,8 double bond
Reduction of 7,8 double bond increases activity
Activity
increases
Activity
increases
OH at C14
7,8 Reduction of double bond
to single bond

11. Hydroxyl at 6
• Modifications at 6 OH which increases activity
1. Removal of Hydroxyl at 6 increases lipophylicity
2. Oxidation of Hydroxyl to keto group at 6 + reduction of 7,8
double bond eg Hydrocodone
3. Acetylation of Hydroxyl at 6 (eg. Heroin)
R= C6 substituent Effect in activity
H Increase 10X
=O (keto)
=O (keto) with 7,8 reduction
decrease (1/3)
Increases (6X )
H3CC=O (acetyl) Increase

12. Hydrocodone
Modifications at 6 OH
which increases
activity

13. Hydroxyl at 6
• Associated with mast cell degranulation 
Histamine release  allergic response
(eg . Codeine – so not given parentrally)

14. Ether linkage
• Removal of Ether linkage produces
compounds called Morphinans that has
increased activity
Activity increases
No ether linkage
Levorphanol
(10X )

15. Morphinans-
Levorphanol,
Potency high
Benzomorphine-
Pentazocine
Potency- low
4-Phenylpiperidines
Mepiridine
Potency low (1/10)
Loss of other rings doesn’t effect analgesic activity.
Aromatic rings

17. Morphine
N- CH3,
phenolic OH,
B/C cis
configuration
potency &
Selective μ agonism
6 αOH – Histamine release 
decrease BP
Lacks 14 β OH- no cough

18. Codeine
• Methyl morphine (Weak µ agonist )
• OCH3  loss of activity  less potent (1/3) .
Thus, used in mild to moderate pain only.
• 6OH- release of Histamine  allergic responses.
Thus not used parenterally.
• Lack of 14 β OH- Used as antitussive drug
• Metabolite is Morphine  abused by addicts

19. Heroin
• Weak μ agonist
• 3,6-diacetyl derivative of morphine
• Two factors make it more potent than morphine
a. Diacetyl form - increases its lipophilicity 
enhances its penetration into brain
b. Metabolite, 6 acetyl morphine, is more active than
morphine
These two factors work together to provide a intense
and quick occuring ‘euphoric rush’ that addicts seek

20. Buprenorphine
• Mixed Agonist/antagonist effect
• N- cyclopropyl methyl group  μ antagonist
overcome by
• Additional hydrophobic & H bonding at C7
– High μ affinity  highly Potency (25X)
– Highly lipid soluble  cross BBB

21. Pentazocine
• Benzomorphine (tricyclic)
• 1st agonist-antagonist to be used as analgesic
(κ agonist & µ antagonist)
• 5C N substitution  μ antagonist
• Missing 6 &7 carbons  compromises its
ability to interact with Receptors weak
analgesic effect (1/5X)

22. Tramadol
• Atypical opiod analgesic
•
• Dual action opiods
(-) isomer blocks norepinephrine reuptake
(+) isomer blocks serotonin reuptake 
analgesic activity. But effect is weak
• Metabolite is active - 1/35X

23. Naloxone
• N-allyl nor oxy morphone
• N –substituent CH2CH=CH2  Strong opiod
antagonist

24. Phenylpiperidines

25. 4- Phenylpiperidines

26. Phenylpiperidines
• Meperidine
• Diphenoxylate 2 important congeners
• Loperamide
• are MOR agonists

27. Anilidopiperidines
• Fentanyls/ Flexible opiods
• Highly lipophylic  rapidly cross BBB  fast &
potent albeit short lived analgesic response
4-(Phenyl propionamido)/
Anilido moiety

29. R1
• N- substituent
• Potent, selective μ agonism
R1 BBB penetration μ Receptor Affinity
Phenethyl
Thienyl ethyl
Increased lipophilicity Increased
Tetrazoline
(polar)
↓pKa  ↓ratio of
ionised- unionised form
 better BBB penetration
Decreased

30. R2
• Methoxy methyl moiety
(Sulfentanyl, Alfentanyl) at C4
of piperidine ring
1. Lipophilic
2. Steric influence promotes
high affinity to receptor

31. Meperidine/
Pethidine
• 4-Phenylpiperidines
• R3= Ethyl carboxylate ester
• Potency- (1/10th)

32. Fentanyl
• Anilidopiperidines
•
• R1 =Phenethyl N substitute
1. 80 times more potent than Morphine (both
analgesia, resp depression)-
2. High lipid solubility  rapidly cross BBB- peak
analgesia in 5min.

33. Thank you