Transcript Document

Analgesia
Altered behavioral response to pain and diminished
ability to perceive pain impulses without loss of
consciousness.
NCH 3
H
Opioid Analgesic Actions:
Analgesia
Decreased G.I. Motility
Respiratory Depression
Euphoria
Classes of Analgesics:
OH
O
OH
Morpheus - son of Hypnos
Non-narcotic – e.g. aspirin, ibuprophen, etc. Act mainly in the periphery as
anti-inflammatories with some CNS activity as well.
Narcotic/Opioids – Analgesic action is in the CNS.
prototype (From “Morpheus” Greek god of dreams).
Morphine is the
Opium is the juice from the poppy and has been used for thousands of
years to relieve pain.
NCH 3
H
OH
O
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
Thomas Sydenham
"Among the remedies which it has pleased
Almighty God to give to man to relieve his
sufferings, none is so universal and so efficacious
as opium." Thomas Sydenham (1624 - 1689)
He was among the first to describe scarlet fever,
differentiating it from measles and naming it, and to explain
the nature of hysteria and St. Vitus' dance (Sydenham's
chorea). Sydenham introduced laudanum (alcohol tincture of
opium) into medical practice, was one of the first to use iron
in treating iron-deficiency anemia, and helped popularize
quinine in treating malaria.
Derided by his colleagues, Sydenham benefited immensely
from a consequent detachment from the speculative
17th century engraving of man in
Eastern dress collecting juice from theories of his time
the buds of poppy plants
NCH 3
H
OH
O
OH
2
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War On Drugs.
Early victims of the War On Drugs. A battle-scene
from the First Chinese Opium War (1839-42)
NCH 3
H
OH
O
OH
3
Davis MDCH 5210 - Analgesics (Opioids) 2005
Endogenous Opioids Endorphins and Enkephalins
Small peptides. -endorphin is a 31 amino acid peptide.
Examples:
Tyr – Gly –Gly – Phe – Met
( Met Enkephalin)
Tyr – Gly –Gly – Phe – Leu
( Leu Enkephalin)
NCH 3
H
OH
O
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
Enkephalin Properties:
•Similar activity to the opioids (analgesia)
•Similar addiction and withdrawal effects
•Enkephalins are antagonized by opioid antagonists (same receptor)
•Enkephalins are rapidly inactivated by specific peptidases in the brain.
Details of Enkephalin Mechanism
•Enkephalinergic system exists to modulate pain.
•Enkephalin release inhibits adenylate cyclase, decreasing cAMP levels and
causing a K+ efflux that hyperpolarizes the “pain neuron”, which inhibits nerve
cell activity. Opioids also bind the enkephalin post-synaptic receptors.
•Enkephalinergic neurons have an “auto-receptor” that can bind enkephalin or
exogenous opioids.
•Opioid binding to the “auto-receptor decreases enkephalin release, this results
in tolerance,
NCH 3
H
OH
O
OH
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Enkephalinergic Neurons
NCH 3
H
OH
O
OH
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Second Messenger Effects - Enkephalin SAR
Second Messenger Effects
Opioids and Enkephalins inhibit cAMP synthesis by inhibiting adenylate cyclase. The
physiological response is to make more enzyme to compensate.
Tolerance develops. When opioids are removed, an excess of AC is available and now
active, overstimulation produces withdrawal.
Opioid antagonists don’t cause withdrawal symptoms in naive subjects.
Enkephalin SAR
L-tyrosine is required along with a terminal NH2.
D-tyrosine is inactive
Phe is very important, partial or full loss of activity occurs upon substitution
D-amino acids at other positions, particularly the Gly’s decrease hydrolysis and therefore
increase potency.
D-amino acids and bulky amino acids affect activity and may increase receptor selectivity
Rigid analogs are useful for assessing preferred conformations and may be more selective
NCH
for different receptors.
3
H
OH
O
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
Analgesic Receptors 
All bind morphine and endogenous enkephalins, all are antagonized by
naloxone
 is the analgesic receptor. 2 subtype is associated with respiratory
depression and with GI receptors.
 may be the antitussive receptor for codeine and related compounds. The
antitussive actions of  and  specific agonists are antagonized by naloxone.
However dextromethorphan sites don’t bind codeine, and binding at these
sites (likely  sites) are not antagonized by naloxone. Therefore, there are
at least two antitussive receptors.
J. Pharm. And Exp. Therapeutics (2000) 292, 803-809
 is also analgesic. Binding site of several mixed agonist/antagonist
compounds.
Pentazocine – agonist at , antagonist at 
Buprenorphine – partial agonist at  (slowly dissociates), antagonist at 
Butorphanol – agonist at , antagonist at 
NCH 3
H
OH
O
OH
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Receptors - continued
 agonists produce psychotomimetic/dysphoric side effects
similar to those seen with the  receptor agonist PCP. High
doses of pentazocine have this effect.
 and  receptors are not analgesic on their own, but specific 
agonists do cause analgesia.
Nature (1996) 383, p.759; pp.819-823.
 knockout does not produce analgesia with morphine, Perhaps
 receptors interact.  binding could induce activity in 
receptors.
Other points:
 (MOR) knockouts are fully functional, no adverse side effects.
Conclusion: opioid system is not active under normal resting
conditions. That’s why you don’t get addicted to your own
enkephalins.
NCH 3
H
OH
O
OH
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Opioid receptors and trans-membrane helices
NCH 3
H
OH
O
OH
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Delta Opioid Receptor Simulation
Figure 3. The starting
configuration for the simulation
of the hDOR in a lipid bilayer
NCH 3
H
OH
O
Mahalaxmi Aburi et al. Protein Sci 2004; 13: 1997-2008
OH
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Receptor Communication
Opioids have excitatory effects in multiple regions of the nervous system.
Excitation by opioids is generally attributed to inhibition of inhibitory
pathways (disinhibition). However, recent studies indicate that opioids can
directly excite individual cells. These effects may occur when opioid
receptors interact with other G protein coupled receptors, when different
subtypes of opioid receptors interact, or when opioids transactivate other
receptors such as receptor tyrosine kinases. Changes in the relative level
of expression of different receptors in an individual cell may therefore
determine its functional response to a given ligand. This phenomenon could
represent an adaptive mechanism involved in tolerance, dependence and
subsequent withdrawal.
NCH 3
H
OH
From inhibition to excitation: Functional effects of interaction between opioid receptors
Life Sciences Volume 76,, (2004), Pages 479-485
O
OH
12
Davis MDCH 5210 - Analgesics (Opioids) 2005
Loss of morphine-induced analgesia, reward effect and withdrawal
symptoms in mice lacking the mu-opioid-receptor gene.
Nature. (1996) 383:819-23.
ABSTRACT: Despite tremendous efforts in the search for safe, efficacious
and non-addictive opioids for pain treatment, morphine remains the most
valuable painkiller in contemporary medicine. Opioids exert their
pharmacological actions through three opioid-receptor classes, mu, delta and
kappa, whose genes have been cloned. Genetic approaches are now available
to delineate the contribution of each receptor in opioid function in vivo.
Here we disrupt the mu-opioid-receptor gene in mice by homologous
recombination and find that there are no overt behavioural abnormalities or
major compensatory changes within the opioid system in these animals.
Investigation of the behavioural effects of morphine reveals that a lack of
mu receptors abolishes the analgesic effect of morphine, as well as placepreference activity and physical dependence. We observed no behavioural
responses related to delta- or kappa-receptor activation with morphine,
although these receptors are present and bind opioid ligands. We conclude
that the mu-opioid-receptor gene product is the molecular target of
morphine in vivo and that it is a mandatory component of the opioid system
for morphine action.
NCH 3
H
OH
O
OH
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NCH 3(R2 )
8
14
7
H
6
1
O
2
5
SAR - 1
NCH 3
H
OH(R1)
OH
O
3
OH(R)
OH
SAR-SAR-SAR-SAR-SAR-SAR
2.
1.
Modifications at the phenolic OH (3-position).
Decrease analgesic potency, increase antitussive activity.
Numbering of morphine is based on phenanthrene.
The important positions, 3,6,7,8,14 are indicated.
1/7 as active compared to morphine for pain. Not a better antitussive.
Codeine only binds 1/3000 the affinity of morphine to  receptor. Analgesic
action is due to morphine.
R = -OCH3
R1 = -OH
3-O-methylmorphine (Codeine)
NCH 3
H
O
R=
O CCH 3
OH
R1 = -OH
3-O-acetylmorphine, 1 x
morphine
O
OH
14
Davis MDCH 5210 - Analgesics (Opioids) 2005
SAR - 2
NCH 3
(NR) H3 CN
NCH 3
14
8
7
H
1
H
H
OH
OH (R1)
O
2
OH
O
6
3
OH (R)
O
OCH3
O
CH3
O
2. Modifications at the alcoholic OH ( 6 position). Substituents increase
potency by increasing liposolubility. Increased potency and addiction.
R=
OH
R=
OCH3
heterocodeine (5 x morphin e)
Poor antitussive
O
R=
OH
R=
R=
OH
R1 = carbonyl
O CCH 3
6-acetylmorphine. 4-5 x
morphine.
morphinone - 1/3 x morphin e
NCH 3
H
OH
O
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
(NR) H3 CN
3. Modifications of both 3 and 6 positions (hydroxyls).
14
R=
O
O CCH 3
R=
6
3,6-O-diacetylmorphin e, 2 x
morphine. (Heroin )
OH (R1)
O
2
O CCH 3
7
H
1
O
8
3
OH (R)
Greater euphoria, higher addiction liability. Probably metabolized to 6-O-acetate
then morphine in CNS.
HEROIN
A powerful remedy for coughs
NCH 3
NCH 3
H
H
O
O
CH 3
O
O
O
OH
O
CH 3
O
NCH 3
H
OH
O
SAR - 3
OH
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(NR) H3 CN
4A. Reduction of the 7,8 double bond. Compounds with same
Substituents at R and R1 and a reduced double bond have the same
potency as morphine. “dihydromorphine”, “dihydrocodeine.”
14
8
7
H
1
6
OH (R1)
O
2
3
4B. Reduction of the 7,8-double bond and oxidation of 6-OH to carbonyl.
R=
Hydromorphone, 7 x morphine
(Dilaudid ). Less sedation, less
R1 = carbonyl
OH
OH (R)
nausea.
R = -OCH3
R1 = carbonyl
NCH3H H
Dihydrocodeinon e,
Hydrocodone, 4 x codeine as an
antitussive. (Dicodid )
NCH3H H
H
H
H
NCH3H H
H
H
H
H
H
OH
O
O
H
O
O
O
NCH 3
H
OH
SAR - 4
OH
OH
OCH3
O
OH
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5. Hydroxylation of C-14, reduction of 7,8-double bond, oxidation
of 6-OH. Generally increases potency.
(NR) H3 CN
14
8
7
H
1
6
OH (R1)
O
2
3
R=
R1 = carbonyl
OH
R = -OCH3
Oxymorphon e (Numorphan). 10
x morphine
Oxycodone (Percodan ) 1 x
morphine as analgesic.
R1 = carbonyl
NCH 3H H
NCH 3H H
H
H
HO
OH (R)
H
H
HO
O
O
O
O
OH
OCH 3
6. Modifications at Nitrogen. 2o N << 3o; 4o Nitrogen is inactive. -N(R) groups larger
than CH3 produce antagonists.
N(R) = N CH 2 CH CH 2
“N-allyl”
N-allyl morphin e (Nalorphine) is
a mix ed agon ist/antagoni st.
“weak or partial agoni st”
NCH 3
H
OH
Nalorphine will compete with more potent agonists to cause withdrawal.
SAR - 5
O
OH
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7. Substitute at Nitrogen plus reduce 7,8-double bond,
hydroxylate C-14, oxidize C6-OH to the carbonyl.
(NR) H3 CN
14
8
7
H
1
6
OH (R1)
O
2
3
N(R) = N CH 2 CH CH 2
N(R) = N CH 2
R1 = carbonyl
Naloxone (Narcan). 7 x better
antagonist than nalorphine.
R1 = carbonyl
Naltrexon e (Traxan) better oral
activity than n aloxone .
CH 2 CH
CH2 CH CH 2
CH 2
N
N
OH (R)
N
OH
OH
H
H
H
H
H
OH
O
O
OH
O
O
O
OH
Etorphine (an oripavine)
200 x Morphine,
Approx. 8000 x Morphine
in animals.
SAR - 6
Puts elephants to sleep.
OH
NCH 3
H 3C
H
CH2 CH2 CH3
OH
OCH 3
NCH 3
H
OH
O
O
OH
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
We need analgesics with less respiratory depression that are also less addictive.
Morphinans.
NCH
NCH
3
H
H
OH
3
H
H
OCH 3
levorphanol (Levo-Dromoran)
(+) or (d) dextromethorphan
(-) isomer is an active analgesic, 5 x
morphine
(+) isomer is an active antitussive
(dextrorphanol) and a poor analgesic
Antitussive activity similar to
codeine, no analgesic activity, no
addiction liability.
N
butorphanol (Stadol)
OH
H
SAR - 7
4 x morphine as agonist
1 x morphine as antagonist
-low(er) addiction liability
“better for acute pain”
NCH 3
H
OH
O
OH
OH
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Benzomorphans.
Pentazocine (Talwin)
N
Mixed agonist/antagonist. Used as
an agoni st for pain. 1/3 x morphine.
Low addiction.
H3C
CH 3
OH
4-phenyl piperidines. Completely synthetic
CH 3
O
OCH 2 CH 3
NCH
N
3
H
NCH 3
OH
OCH 2 CH 3
O
O
NCH 3
OH
H
Meperidine
SAR - 8
OH
Meperidine
Morphine
O
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
4-phenyl piperidine SAR.
•Phenyl and piperidine rings are required.
•3° Nitrogen is optimal. Nitrogen substituent containing a phenyl group increases
potency (fentanyl).
•You can’t make an antagonist by substituting the nitrogen.
•Addition of a meta hydroxyl to the aromatic ring increases potency and addiction
(analogous to morphine)
•C-4 is usually quaternary. Alkyl esters are common for this class. Placing a nitrogen
between the rings increases potency (fentanyl again)
Properties of Phenylpiperidines.
Bemidone – 3 x Meperidine
-Prodine (Nisentil) – 2 x Meperidine. Not used anymore
Fentanyl (Sublimaze) – ~50-100 x Morphine. Fast onset, short duration. Used as
an analgesic and also as an anesthetic either with or without droperidol. (About
500 x Meperidine analgesic potency).
Diphenoxylate – Antidiarrheal – Not analgesic at therapeutic doses and can be
dispensed with Atropine
Loperamide (Imodium) – Polar groups decrease intestinal absorption and eliminate
CNS activity. Inhibits GI muscle contraction by interaction with opioid receptor.
NCH 3
H
OH
O
OH
SAR - 9
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OCH2 CH3
O
NCH3
O
OCH2 CH3
HO
N
Bemidone
CN
OCH2 CH3
O
Diphenoxylate
NCH3
H3 C
-prodine
O
HO
O
Cl
N
CH2 CH3
N(CH3 )2
N
N
Loperamide
Fentanyl
F
N
O
NCH 3
N
H
O
SAR - 10
OH
O
N
OH
Droperiodol (a butyrophenone, not a phenylpiperidine)
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3,3- Diphenylpropyl amines.
Methadone
1x morphine
less sedative
longer acting. 1, 1.5 day half-life. 1 dose every 72 hours will prevent
heroin withdrawal
Propoxyphene
d isomer (Darvon) – analgesic with 1/2 the potency of codeine
l isomer (Novrad) – antitussive action only.
CH3
C
CH 3
CH3
CH2 CH N
CH2
CH2CH 3
Methadone
CH
CH 2
N
CH3
O
CH3
O
C
CH3
O
NCH 3
CH 2CH3
Propoxyphene (d or l isomer)
H
OH
O
SAR - 11
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
Fentanyls
O
O
O
N
O
O
O
N
N
N
O
N
N
N
N
N N
O
O
O
O
Remifentanil
Alfentanil
Fentanyl
O
O
N
O
N
N
N
S
Sufentanil
Carfentanil
Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100 g/h) Therapeutic
index=400, morphine = 70
Alfentanil - Ultra-short acting, 5-10 minutes analgesic duration
Remifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000
Sufentanil - 5-10x Fentanyl, used for heart surgery.
Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue
Chechen hostage takers. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears.
NCH 3
H
OH
O
OH
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Davis MDCH 5210 - Analgesics (Opioids) 2005
NCH 3
H
OH
SAR - 12
O
OH
26
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NCH 3
H
OH
SAR - 13
O
OH
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