Beruflich Dokumente
Kultur Dokumente
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
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
E
D
B
C
Methadone
Morphinans
Benzomorphans
4-phenylpiperidines
Loss of activity
Codeine
Heroine
Levorphanol
Phenazocine
Pentazocine
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)
Naltrexone
Nalorphine
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
Brain
Analgesia, antidepression,
dependence
Receptor binding -
Opening of the K+
channel
hyperpolarizes the
membrane
Morphine
Reduces
neurotransmitter
release
Receptor Binding -
Morphine
Binding causes
closing of Ca+2
channels
Neurotransmitters
not released
Pain message not
sent
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