The document discusses the chemistry and structure-activity relationships of opioid analgesics, particularly focusing on morphine and its analogs. It details modifications to the morphine structure that affect potency and activity, such as changes at the hydroxyl groups and the introduction of acetyl groups, leading to compounds like heroin and other analogs. Various morphine derivatives are compared in terms of their effectiveness, side effects, and intended medical uses, highlighting the importance of molecular structure in opioid efficacy and safety.

1. Chemistry of Opioid Analgesics
Well known for their ability
to reduce the perception of
pain without a loss of
consciousness.

2. * increase in the tolerance to pain,
* somnolence (alternatively "sleepiness" or
"drowsiness"),
* euphoria, an antitussive effect, respiratory
depression,
* constipation and emesis.
* high addiction liability.
Variety of Effects

3. The structure of morphine
O
OH
HO
N
H
CH3
B to C ring fusion cis
C to D ring fusion trans
(-)-5R, 6S, 9R, 13S, 14R stereochemistry
Morphine
A
B
C
D
E
3
6
7
8
14
9
10
11
12
13
1
2
4
5
The rings are lettered
A (aromatic),
B (cyclohexane),
C (cyclohexene),
D (piperidine) and
E (tetrahydrofuran).

4. 1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
OR
H
HO
NCH3
H
Alcohol
Phenol
Amine
Ether
Potential Binding Groups
Aromatic
ring
Alkene

5. Opium contains
 morphine,
 codeine,
 noscapine,
 papaverine, and
 thebaine.

6. Structure/Activity Relationships
 Mask or remove a functional group
 Test the analogue for activity
 Determines the importance or other wise
of a functional group for activity

7. 1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
OR
H
HO
NCH3
H
Modifications at the 3- hydroxyl groups:
Structure/Activity Relationships of Morphine Analogues
R=Ac 3-Acetylmorphine
Decreased activity
•Acetyl masks the polar phenol group
•Acetyl group is hydrolysed in the brain to form morphine
R=H Morphine
R=Me Codeine
Decreased activity

8. Conversion of the 3-OH to a 3-OCH3,
yielding codeine,
reduces activity to 15% of morphine.
Groups larger than a methoxy reduce
activity dramatically.
Notes
Compound crosses the blood brain
barrier more easily

9. Conclusion
Masking phenol leads to poor
activity

10. Modifications at the 6- hydroxyl groups:
1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
OR
H
HO
NCH3
H
Removal of the 6-OH (6-desoxymorphine) increases
activity 10-fold in the dihydro series.

11. Conversion of the 6-OH to a 6-OCH3, yielding
heterocodeine, results in a six-fold increase
in activity.
Oxidation of the 6-OH to a ketone reduces
activity when the 7,8-double bond is present
(morphinone = 37% of morphine).
However, as shown below, when the 7,8-
double bond is saturated, a 6-keto will
increase activity.

12. 1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
OR
H
HO
NCH3
H
1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
O
H
HO
NCH3
H
1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
H
HO
NCH3
H
•Activity increases due to reduced polarity
•Compounds cross the blood brain barrier
more easily
•6-OH is not important for binding

13. 1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
OR
H
HO
NCH3
H
Alcohol
Phenol
Amine
Ether
Potential Binding Groups
Aromatic
ring
Alkene

14. 1
2
3
4
5
6
7
8
9
10
11
12
13 14
O
OR
H
HO
NCH3
H
6- Alcohol
NOT REQUIRED
N-Methyl Group (Amine)
REQUIRED
Ether bridge
NOT REQUIRED
Aromatic ring
REQUIRED
(Alkene)
Double bond at 7-8
NOT REQUIRED
Phenolic OH
REQUIRED
Morphine - SAR

15. O
O
RO
N
H
CH3
R = H, dihydromorphinone
(6 X as potent as dihydromorphine)
R = CH3, dihydrocodeinone
(4 X as potent as dihydrocodeine)

16. O
O
N
H
CH3
O CH3
O
O
H3C
Acetylation of both the 3- and 6-OH produces 3,
6-diacetylmorphine, also known as heroin.
Most of this increase is due to increased lipid
solubility, which leads to enhanced and rapid
CNS penetration
R=Ac Heroin
Increased activity (2x)

17. O
HO
N
H
CH3
O CH3
O
Activity
4x that of morphine!
Polarity decreased, but phenol
is ready to bind receptor
Side effects: Very potent!!
Euphoria, addiction, etc.
Marketed as:
NOTHING! It’s banned from
production in many
countries

18. Morphine Analogues - Morphinans
How it’s related:
Ether bridge removed
Activity:
5x that of morphine
Advantage:
It can be taken orally
Lasts longer
Easier to synthesize
Side effects:
High toxicity, comparable
dependence
Levorphanol

19. Morphine Analogues - Benzomorphans
How it’s related
Rings C and D removed
Activity
4x + that of morphine
Advantages
No addictive properties
Does not depress breathin
Lasts longer
Side effects
Hallucinogenic
Marketed as
Prinadol, Norphen
Fortal, Talwin NX
Phenazocine
Pentazocine

20. Fentanyl
Morphine Analogues – 4-phenylpiperidines
Fentanyl
How it’s related:
Rings B,C,D removed
Activity:
100x that of morphine
Advantages:
Cross BBB efficiently
Really easy to make
Rapid onset, short
duration
Can be administered any
way (IV, oral, transdermal,
buccal)

21. Morphine Analogues – 4-phenylpiperidines
Used for:
Anesthesia
Chronic pain management
Side effects:
Sudden respiratory depression
More addictive than heroin
Less euphoria, more sedation
Marketed as:
Sufenta (used in ♥ surgery)
Carfentanil (used in vet
practice)
“Percopop”, OxyContin,
“magic” (heroin/cocaine)

22. Morphine Analogues - Methadone
How its related:
Rings B,C,D,E opened
Activity
< Morphine
Used to:
Ween addicts off heroine or
morphine
Advantages:
Can be given orally
Less severe side effects
Marketed as
Dolophine®, Amidone®,
Methadose®

23. Morphine analogues - Naltrexone
How it’s related:
Cyclopropylmethylene
added to morphine
Activity:
None?!
Morphine antagonists
Used to treat:
Morphine overdose
Heroin addicts post-rehab
Advantages:
No side effects
Marketed as:
Revia, Depade, Vivitrol
Naltrexone
Nalorphine