Download Lec.5-426

MEDICINAL CHEMISTRYIII
Lecture 5
Wed. 23/ 5/ 1432H
Prof. Dr. Wafaa Zaghary
Analgesic
1. A basic center …..
2. A flat aromatic structure,
…….
3. A suitably positioned projecting hydrocarbon moiety ….


Receptor of opiates
Morphine has 3 receptors:Mu
(µ) the main receptor for analgesic & side effects
Kappa (ķ) weak analgesic effect
Delta (δ) weak analgesic effect

Morphine binds to its receptors in the brain
through 3 main binding sites:a. Van der Waal forces
Ring A
b. H Bonding
Phenolic OH
c. Ionic bonding and cavity for C-15 and C-16
Structure Activity Relationships
Modification at 3oH and 6-OH

Methylation of the phenolic OH reduces the analgesic
activity considerably (thus codeine is about 6-10 times
less potent)
Larger group than
methoxy

reduces activity
drastically
N.B. Alkylation of phenolic OH e.g. Codeine, Dionine,
Pholcodine decrease activity due to ……………………..
•
Diacetylation (heroin) yields a more potent drug than
morphine. This may be due to the fact that the
phenolic acetate, which is cleaved in-vivo yields the
potency intermediate 6-acetymorphine (4x)
Heroin (2-3 x).
•
6-acetyl morphine present the desirable features of
increased potency due to:
1. increased lipophilicity.
2. phenolic OH is free to bind to the receptor.



Aromatic ring is essential for activity,
reduction or removal abolishes activity.
Ether bridge is not essential, Compounds
lacking this ring are called morphinans and are
several folds more active than morphine.
Oxidation of the OH at 6-position to a ketonic
function particularly if the 7-8 double bond is
also reduced affords a more potent drug
(hydromorphone).


Introduction of OH group to hydromorphone at C-14
Oxomorphone
Oxocodone
Oxomorphone is several times more active than
morphine.
Chemical Name …………………
Modification at 17-N



Any exchange of N-methyl group with larger alkyl, alkenyl and
arylalkyl function giving different activity depending on the size
of alkyl group.
the bulk of the alkyl group < 3C
Activity
e.g. N-CH3
N-C2H5
If the alkyl group = 3C
Antagonist character.
e.g. N-CH3
N-CH2-CH=CH2 , the activity is ………….





Nalorphine acts as antagonist & partial agonist.
Nalorphine is used in treatment of morphine addiction and
respiratory depression.
Nalorphine acts at two opioid receptors, at the mu receptor it has
antagonistic effects and at the kappa receptors it exerts agonistic
characteristics. It is used to reverse opioid overdose and (starting in
the 1950s) in a challenge test to determine opioid dependence.
Block the main receptor for analgesic activity at mu
Antagonist
Open kappa receptor
partial agonist
Antagonists





Modification of Nalorphine
OH at C-14
convert oh at C-6 into keto group
i.e. replacement of alkyl in position 17 of Oxomorphone by allyl
group
Naloxone block all receptors [(µ), (ķ)& (δ) ]
Naltrexone


Pure antagonist
It can displace morphine from all these receptors
N
HO
HO
O
O
Removal of alkyl group
Normorphine
……… demethylation at N-17
……… more polar ………….. Lipophilicity ………. Activity.
Also, quaternization at position 17
the activity due to …..
Morphine Rule

1.
2.
3.
From SAR of morphine, it was reached to a
generalization known as morphine rule for
an opioid to be active, it will have the
following characteristic:Central Quaternary carbon
attached to phenyl group
and separated from tert. nitrogen by a bridge
of 2 carbons.
Structure Activity Relationship
1. A tertiary nitrogen, with the group on the nitrogen
being relatively small
2. A central carbon atom
3. A phenyl group or isosteric group with phenyl,
connected t central carbon atom
4. A two carbon chain separating the central carbon
atom from the nitrogen for maximal activity