Opioid Analgesics

Mallika Doss
April 10, 2008

Overview

History
Morphine
SAR of Morphine
Drug Dissection of Morphine
Morphine Analogues
Opioid Receptors & Receptor Binding
Agonists and Antagonists
Why you feel happy
Endogenous Opioid peptides
The Future

The History

First use in Mesopotamia

First recorded use in China
632 AD Opium reaches Spain, Persia, and India
17th century Tobacco comes to China
1644 Chinese emperor bans tobacco
19th century China closes its doors to the world
Deprived of tobacco, Chinese people start smoking opium!
Opium production in China couldnt keep up with demand.
British East India company sees opportunity.
1830s 1 million of opium smuggled into China via Port
Canton.

The History
Chinese authorities burnt down the port; British traders
outraged.
1839-42 Opium Wars; Chinese were defeated and
forced to lease trading port to Britain.
19th century Opium dens common in Britain.
1882 Addictive properties of opium discovered but
largely ignored.
1909 IOC set up to curb opium production
1924+ Opium production went underground

Morphine
Named after the Greek God,
Morpheus (God of dreams)
Good for treating dull, constant pain
rather than sharp, periodic pain
Side effects:
Excitation
Maximize
Euphoria
Nausea
Pupil constriction
Constipation
Minimize Tolerance and Dependence
Depression of breathing

Morphine - SAR
Phenolic OH
Required
Ether bridge
Not Required
6-alcohol
Not Required

Aromatic ring
Required
N-methyl group
Required

Double bond at 7-8

Not Required

Morphine Drug Dissection

Activity retained

E
D

B
C

Methadone
Morphinans
Benzomorphans
4-phenylpiperidines

Loss of activity

Morphine Analogues - Codeine

Codeine

How its related

Methyl ether of morphine
Activity
20% that of morphine
Pro-drug of morphine
Metabolized by Odemethylation in the liver
to make morphine

Morphine Analogues - Codeine

Treats:
Moderate pain
Coughs
diarrhea
Marketed as:
Tylenol with Codeine
Hydrocodone
Vicodin (with
Thebaine)

Morphine Analogues - Heroine

Heroine

How its related:

3,6-diacetyl ester of morphine
Activity:
2x that of morphine
Polar groups are hidden, making it
easy to cross BBB.
Treats:
Pain in terminally ill patients
Side effects
Euphoria, addiction, tolerance
Marketed as:
Heroin, dope

Morphine Analogues - Heroine

6-acetylmorphine
How its related:
6-acetyl of morphine
Activity
4x that of morphine!
Polarity decreased, but phenol is
6-acetylmorphine
ready to bind receptor
Side effects: Very potent!!
Euphoria, addiction, etc.
Marketed as:
NOTHING! Its banned from
production in many countries

Morphine Analogues - Morphinans

Levorphanol

How its 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
Marketed as
Levo-Dromoran

Morphine Analogues Benzomorphans

How its related
Rings C and D removed
Activity
4x + that of morphine
Advantages
No addictive properties
Does not depress breathing
Lasts longer
Side effects
Hallucinogenic
Marketed as
Prinadol, Norphen
Fortal, Talwin NX

Phenazocine

Pentazocine

Morphine Analogues 4phenylpiperidines

Fentanyl

Fentanyl
How its 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)

Morphine Analogues 4phenylpiperidines

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)

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

Morphine analogues - Naltrexone

How its 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

Agonists and Antagonists

Equatorial Antagonist
binding area

Axial Agonist binding area

SIDE NOTE:
Other factors important to receptor binding:
Stereochemistry
Enantiomers of many of the analogues were tested
for analgesic activity. Overall, they didnt have any.
Rigidification
Used to maintain active formation and eliminate
alternative conformations
Increases selectivity for receptors

Opioid Receptors
Receptor-binding
motif:
Phenol OH
Aromatic ring
Amine group

Opioid Receptors
Most
strongly
binds
morphine
Best bet
for a safe
analgesic

Receptor Location
type

Effects

Brain,
spinal cord

Analgesia, Respiratory
depression, euphoria, addiction,
ALL pain messages blocked

Brain,
spinal cord

Analgesia, sedation, all nonthermal pain messages blocked

Brain

Analgesia, antidepression,
dependence

Receptor binding -
Opening of the K+
channel
hyperpolarizes the
membrane

Morphine

Action potential not

sent

Ca+2 not released

Hyperpolarized!

Reduces
neurotransmitter
release

Receptor Binding -
Morphine

Binding causes
closing of Ca+2
channels
Neurotransmitters
not released
Pain message not
sent

Why you feel happy

Why you feel happy

Heroin modifies the action of dopamine in the brain.
Once crossing the blood-brain barrier, heroin is
converted to morphine, which acts as an agonist.
This binding inhibits the release of GABA from the nerve
terminal, reducing the inhibitory effect of GABA on
dopaminergic neurones.
The increased activation of dopaminergic neurones and
the release of dopamine into the synaptic cleft results in
activation of the post-synaptic membrane.
Continued activation of the dopaminergic reward
pathway leads to the feelings of euphoria and the high
associated with heroin use.

Endogenous Opioid Peptides

Your bodys natural
painkillers
Have a preference for the receptor
Alternative method of pain
relief inhibit the
Met-enkephalin
peptidases that degrade
them thiorphan (still new)
3 types of EOPs:
Enkephalins
Dynorphins
Endorphins

The Future
Find an agonist that solely binds to the -receptor
Explore the -receptor subtypes further to see if any of
them dont cause harmful side effects
Peripheral opiate receptors avoid BBB obstacle
Block postsynaptic receptors involved in the
transmission of a pain signal
GABA
Agonists for the cannabinoid receptor

References