The document discusses the structure-activity relationships (SAR) of opioids, with a focus on morphine as the prototype and its various modifications. It highlights the importance of specific functional groups on the opioid molecule for efficacy and activity at mu and kappa receptors. Various derivatives such as codeine, heroin, hydromorphone, and oxymorphone are examined for their structural modifications and resulting pharmacological effects.

1. Structure activity relationship of opioids
Dr.Ameya Puranik
Junior Resident
JNMC,Sawangi(M),Wardha.

2. Introduction
• Natural opioids are opium or extracted from poppy straw.
• Powdered opium contains number of alkaloids divided in two distinct
groups
1) Phenanthrenes- Morphine,Codeine,Thebaine
2) Benzyllisoquinolines- Papaverine,Noscapine
• Most of the semi-synthetic and synthetic derivatives are made by
structural modifications of Morphine or Thebaine.
• Morphine is considered as a prototype structure to study structural
activity relationship of opioids.

3. Classification based on structure

4. Morphine(prototype)
• Its is a primary alkaloid in opium family
• Pentacyclic carbon ring structure
• Only levorotatory isomer is active
Its has six functional groups:
• A tertiary nitrogen
• Hydroxyl group attachment at (C3)
• Hydroxyl group attachment at (C6)
• Ether group
• Double bond between C7-C8
• Hydrogen atom at (C14)
• N-methyl is mainly responsible for analgesic
effect

5. Morphine numbered structure

6. “Morphine rule”
It is developed for generalization of structure activity relationship of
various opioids, for the opioid to be active it should have atleast
following characteristics in the structure:
• A tertiary nitrogen atom.
• A quarternary carbon,seperated from tertiary nitrogen by a bridge of
two carbons.
• Phenyl group attachment.

7. Phenolic hydroxyl group (C3)
• It is needed for binding to Mu & Kappa receptors.
• Seen in all potent Mu-agonists.
• Changes at phenolic hydroxyl group:
-OH -OCH3 (1/3) Decrease in activity(eg.Codeine)

8. Codeine
• Naturally occurring opium
• Replacement of –OCH3 at C3
• Also known as 3-methyl ether morphine.
• --OCH3 causes weak Mu-agonist activity.
• Analgesic activity reduced to 10%,but antitussive
activity is retained.
• --OH at C6 causes histamine release and allergic
response if given parentally.

9. HEROIN
• Acetylation of both the 3- and 6-
OH produces 3,6-
diacetylmorphine,also known as
heroin.
• This causes increased lipid
solubility,which leads to
enhanced and rapid CNS
penetration.
• Hence heroine is rapidly action
and causes euphoric rush.

10. (C14)H/OH moiety
• Addition of –OH group at 14 position
causes:
1)Increase in activity by 2-3 times
2)Increases penetration of blood brain
barrier
3)Decrease in anti-tussive action

11. 7,8 double bond

12. Hydroxy group at (C6)
Modifications at C6:
• Removal of –OH cause increase in lipophilicity.
• Oxidation of hydroxyl group to ketone group eg. Hydromorphone and
hydrocodone.
• Acetylation of hydroxyl group eg. Heroin.
• -OH group at C6 alone is associated with histamine release hence
causes allergic response if given parentally eg.Codeine.

13. Hydromorphone
Two structural changes:
• Ketone bond at C6
• 7-8 double bond has been reduced to a single
bond,by adding two hydrogen atoms(not shown)
reduction of 7-8 + ketone at C6 Dihydro-morphine-one
(dihydro) ( -one)
• Both changes causes increase in activity by 6 times

14. Oxymorphone
Three structural changes:
• Ketone bond at C6
• 7-8 double bond has been reduced to
a single bond,by adding two
hydrogen atoms(not shown)
• -H at C14 is replaced by –OH group
• OXY-MORPH-ONE . The oxy refers to
–OH on C14
-OH at C14 causes:
• Increase in activity(2-3x),increase in
BBB penetration.
• Decrease in antitussive effect.

15. Oxycodone/Hydoxycodone

16. Ether linkage

17. Aromatic rings

18. N-Methyl group
• Nitrogen group have major effects on pharmacological
activity of opioid
• Narcotic anatagonists are made by using oxymorphone
structure with modified substituents on the nitrogen
The Nitrogen is mostly tertiary with a methyl substitution
in morphine. The size of substituent on Nitrogen dictates
potency and agonist or antagonist activity.
a) Increasing size from methyl (i.e. 1 C) to 3 or 5 carbon
(especially with double bonds or small cyclic/aromatic
rings) results in antagonist activity
b) Further larger substitution restores agonist activity in
more potent form(eg.Etorphine LD50 is 30mcg)

20. Thank you