PHA051 LAS#9

RATIONALE
1. Describe the SAR of morphine
A. A rigid pentacyclic structure
consisting of a benzene ring (A), two
partially unsaturated cyclohexane rings
(B and C), a piperidine ring (D) and a
dihydrofuran ring (E). Rings A, B and C
are the phenanthrene ring system.
This ring system has little
conformational flexibility. Ring A and its
3-hydroxyl group is an important
structural feature for analgesic activity.
Removal of the 3-OH group reduces
analgesic activity by 10-fold.
B. Two hydroxyl functional groups, a C3-phenolic OH (pKa 9.9) and
a C6-allylic OH.
C. An ether linkage between C4 and C5.
D. Unsaturation between C7 and C8.
E. A basic, 3°-amine function at position 17
F. 5 Centers of chirality (C5, C6, C9, C13 and C14) with morphine
exhibiting a high degree of stereoselectivity of analgesic action.
Only (-)-morphine is active.
Morphine as well as a majority of narcotic analgesics are
functionally basic compounds both pharmaceutically (dosage forms)
and physiologically due to the presence of tertiary amine functions .
Hence, morphine exists as a cation at physiologic pH, and readily
forms salts with appropriate acids (commercial products are sulfate
and HCl):
2. Discuss the modifications in the structure
of morphine in order to yield:
A. Heroin- Esterification (acetylation) of both the 3- and 6-OH
groups yields heroin, which is more lipophilic and more potent.
The primary factor involved in increased analgesic potency is the
increased lipophilicity and distribution to the CNS.

Heroin is synthesized from morphine by a relatively simple

esterification reaction of two alcohol (phenol) groups with acetic
anhydride. Heroin is much more potent than morphine but
without the respiratory depression effect. Acetyl groups are
readily removed by metabolism to active morphine. Heroin is
official as hydrochloride salt. It occurs as water soluble, white
crystalline, bitter taste powder.
B. Codeine
• Conversion of the 3-OH to a 3-OCH3, yields
codeine, reduces activity to 15% of morphine.
Codeine is available as a sulfate and
phosphate salt and also as the free base and
as tablets, elixir and solution for injection.

• The 3-methoxy group protects the 3-position

from glucuronide as occurs with morphine.
Codeine is used as an analgesic and
antitussive.
 C. Hydromorphone and oxymorphone
• The 7, 8-double bond of morphine also is not required for
analgesic activity as indicated by the relative analgesic
potency of dihydromorphine.
• Also, oxidation of the 6-OH of dihydromorphine to yield
hydromorphone further increases activity.
• Substitution of a 14-OH group on the hydromorphone
structure as in oxymorphone produces a further increase in
analgesic activity
• Oxidation of the 6-OH of morphine directly as in morphone
(without reduction of the 7, 8-double bond) does not
significantly alter analgesic activity.
D. Dihydrocodeine and Oxycodone
• Reduction of codeine’s 7, 8-double bond as in
dihydrocodeine increases activity relative to
codeine.
• Oxidation of the 6-OH of dihydrocodeine as in
hydrocodone results in a further increase in
activity, and 14-OH substitution produces a further
increase in analgesic activity
E. Thebaines
The Thebaines. Adding a sixth ring across
carbons 6 and 14 of the C ring of morphine
yields thebaine compounds such as etorphine
which are extremely potent analgesics.
Replacement of the N-methyl group of the
thebaines with a methylcyclopropyl group yields
compounds with mixed agonist/antagonist or
partial agonist activity.
 3. Explain the metabolism of morphine
and codeine.
• Morphine is extensively metabolized via phase II conjugation
to morphine-3-glucuronide (60%), morphine-6- glucuronide
(9%), and, to a lesser extent, the N-demethylated metabolite
(3%)
• Much controversy exists on the contribution of the
metabolites of both codeine- 6-glucuronide and morphine-6-
glucuronide to their analgesic effect.
• In some studies, the 6-glucuronide metabolite of both drugs
contributes significantly to their potency.
• In other studies, the 6-glucuronide metabolites of morphine
and codeine produces very little analgesic effect.
4. Describe the structure of the ff. and
enumerate the drugs under each class
B. MORPHINANS
- The morphinans were made by
removing the E ring of morphine, the
4,5-ether bridge, in an attempt to
simplify the structure
- Levorphanol, dextromethorphan
C. Benzomorphans

• Structural simplification of
the morphine ring system
further, by removing the C
ring of the morphinan
structure, yields the
benzomorphans also
referred to as the
benzazocines.
- pentazocine
D. 4-Phenylpiperidines and 4
Anilidopiperidines
• Further structural simplification of the benzomorphan
ring system, via removal of the B ring of the
benzomorphans yields the 4-substituted piperidines.
• The resultant structures are flexible and, without the B
ring locking the A ring in an axial position relative to the
piperidine (D) ring, the A ring can exist in either an axial
or an equatorial position
E. DIPHENYLHEPTANES
METHADONE
Methadone (Dolophine)
is a synthetic opioid
approved for analgesic
therapy and for the
maintenance and
treatment of opioid
addiction
PROPOXYPHENE

is a derivative of
methadone
 F. Miscellaneous
TRAMADOL
- Structurally, tramadol
resembles codeine with the B,
D, and E ring removed. The
manufacturer states that
patients allergic to codeine
should not receive tramadol,
because they may be at
increased risk for anaphylactic
reactions
G. Mixed Agonist/Antagonist
Nalbuphine
Nalbuphine (Nubain) is
structurally a member of the
phenanthrene class of
compounds and resembles
oxymorphone with a
cyclobutyl methyl group on
the nitrogen, equivalent to
naloxone’s substitution.
Butorphanol

• Structurally, butorphanol is
a morphinan and shares
the same cyclobutyl methyl
group on the nitrogen as
nalbuphine.
Buprenorphine
•Buprenorphine is a
semisynthetic,
highly lipophilic
opiate derived
from thebaine
*Opioid Antagonists (special topic)

•Replacement of the potent narcotic agonist

oxymorphone’s N-methyl group with an allyl
group (—CH2—CH = CH2), a
methylcyclopropyl group or a
methylcyclobutyl group also results in the
emergence of opiate receptor antagonist
activity. Ex: naloxone HCl, naltrexone HCl,
methylnatrexone, & nalmefene.
5. What are the therapeutic uses
of opiates?
1. Analgesia. reduces perception and
emotional response to pain.
2. Intestinal disorders. reduce diarrhea
and avoid dehydration.
3. Antitussive. cough suppressant
(codeine).
6. Give the adverse effects of opiates.

1. Respiratory depression. Medulla in brainstem

becomes less responsive to carbon dioxide in
blood; additive with other depressants.
2. Drowsiness and decreased mental alertness.
3. Constipation.
4. Nausea and vomiting.
5. Tolerance. Cross tolerance with similar
opiates.
6. Acute Toxicity.
7. Narcotic Triad. Coma, respiratory depression,
pin point pupils
8. Physical dependence. “flu-like” withdrawal
effects; rarely life threatening. Severely addicted
subjects report significant pain.
9. Psychological dependence. Positive
reinforcement from euphoria and negative
reinforcement from rapid appearance of
withdrawal symptoms