Transcript PHARM4515-15 (Opioids)

Opioids
Opium poppy cultivation
Opium poppy capsule (Papaver
Namut Ali inhales heroin in a cemetery
somniferum), the source of both opium near Quetta. Heroin coming across the
and the poppy seeds you find on bread Afghan border to Pakistan costs only about
$1 a gram. (By Adrees Latif, Reuters)
History

Papaver somniferum

The term opium is from the Greek opion, meaning, poppy juice, Papaver is
from the Latin name for the poppy, and somniferum is Latin, meaning, to
produce sleep

Morphine was first isolated in 1803 from juicy exhudates of poppy by Friedrich
Serturner, a pharmacist, and named after Morpheus, the Greek god of dreams

Characterized in 1925

Codeine was isolated in 1832 and papaverine in 1848

Two major types of alkaloids: phenanthrenes (1), e.g., epoxymorphinans or
morphine), and the benzylisoquinolines (2)
CH3
H3C
N
H3C
N
O
O
N
O
1
HO
2
O
Morphine
OH
O
Papaverine
CH3
CH3
CH3
N
CH3
CH3
O
HO
N
N
OH
Morphine (1925)
CH3
N
HO
O
O
Levorphanol (1946)
OH
CH3
CH3 O
O
Codeine (1929)
CH2
CH3
Alphaprodine (1946)
N
N
HO
HO
O
OH
Nolorphine (1941)
N
H3 C
N
Levallorphan (1951)
O
Fentanyl (1964)
N
CH2
N
CH3
CH3
OH
HO
Phenazocine (1959)
HO
O
O
Naloxone (1963)
Genesis of new
narcotic agonists
and antagonists
through molecular
modification
Opiate/Opioid

“Opiate” (used until 1980s) means drugs derived from opium – morphine,
codeine, and their semi synthetic analogs

“Opioid” was coined after discovery, in the mid-1970s, of peptides in brain
that had morphine–like pharmacologic activity that include natural and
synthetic compounds and peptides

Opioid receptors - that bind these opioids to elicit morphine-like agonistic
or antagonistic activities

“Narcotic” derived from the Greek word, narkōtikos, meaning to be numb,
and was originally applied to any drug which induced sleep

Thus morphine–like analgesics (opioids) are called narcotic analgesics

narcotic was also defined legally (Harrison Narcotics Act, 1914) and it
was used to refer to drugs, such as opioids, cocaine and marijuana, that
were controlled in a more stringent manner than other drugs

Now they are classified by DEA as Schedule I drugs
Opioid Peptides
O
HO
NH2
N
H
H
N
O
O
O
N
H
O
HN
O
H2N-Tyr-Gly-Gly-Phe-Leu-COOH
Leu-enkephalin
HO
OH
NH2
N
H
H
N
O
O
N
H
O
HN
O
S
OH
H2N-Tyr-Gly-Gly-Phe-Met-COOH
Met-enkephalin

Greek, kephalē, which means “head” gives the name enkephalins. 2
enkephalins differ in the fifth amino acid one has a Methionine and the other
a Leucine residue: Met–enkephalin and Leu–enkephalin

pro–enkephalin and few more endogenous peptides with opioid activity have
been found, the endorphins and the dynorphins,

The opioid receptor has been subtyped into three distinct types based on
these three types of endogenous peptides: (Endorphins –Mu, dynorphins –
kappa, enkephalins – delta)

In all three types of peptides the amino terminus is always the same four
amino acids (H2N–Tyr–Gly–Gly–Phe–)
Opioid Receptors
Three major subtypes of opiate receptor
•
μ (Mu, OP3): the most important receptor, Encoded by the MOR-1 gene,
subtyped into μ1 and μ2. Agonists cause Supra–spinal & spinal analgesia,
respiratory depression, euphoria, emetic effects, physical dependence, and
constipation. Morphine and endorphines are selective agonist and naloxone is
selective antagonist
•
δ (Delta, OP1): Encoded by the DOR-1 gene. Subtyped into δ1 and δ2. Spinal
analgesia, GI motility, motor integration, cognitive functions, mood driven
behavior are the agonist properties. D-Ala-D-Leu-enkephalin is a selective
agonists while naltrindole is a selective antagonist
•
κ (Kappa, OP2): Learning & memory, spinal analgesia, sedation,
neuroendocrine secretions. N/OFQ or ORL-1 receptor. Dynorphins are
selective agonists.
.
Schematic Representation of an Opioid
Receptor
Site” D” binds the
tyrosine residue of the
endogenous opioid
peptides: Flat,
hydrophobic with an
adjacent hydrogen
bonding site for hydroxyl
on phenyl ring that binds
ring “A” of morphine
Site “A” is an additional lipophilic
site that binds with the phenyl ring
on phenylalanine of the
endogenous opioid peptides. This
explains receptor interaction of
some of the opioid drugs
Site “B” is an anionic site that
binds the protonated nitrogen
of the pyridine ring (ring “D”)
found in morphine
Site “C” is a cavity that
accomodates C15 of morphine
Ring Nomenclature and Numbering
R1
R1
N
2N
8 3
4'
3'
7
Removal
of ring C
1
2
6
5
1'
HO
R1
R1
1N
3
R3
1N
6
2
5
6'
5'
4
N
4'
R2
3'
R2
10 16 9
14
1 11
B15 D
R3
8
12
2
A
13 C 7
6
E
3
5
4
O
O
3
3
6
R1
N
10
1
B5
R3
Phenylpiperidine
3
N
Removal
of ring D
CH3
R3
R4
Anilopiperidine
R2
R1
Phenylpropylamine
11
A
2
H 3C
R2
13 C 8
5
7
4
Adding
a ring F
R4
R3
Morphinan
6
4
2'
O
O
Epoximorphinan
1'
A
Removal
of ring E
N
Removal
of ring B
R2
12
A
R2
R3
Benzmorphan
2
1
B 4C 9
A
2'
R1
10 16 9
11
14
B15 D
HO
16
B
15
9
D
12 13
4
E
O
14
F
8
18 C
17
5
7
R2
6
Oripavines
O
CH3
Epoxymorphinans
10
1
A
2
3
R2
11
O
CH3
N
N
16
9
D14 R3
C 87
13
15
B
12
4
R1
E
O
6
5
O R4
General structure
HO
O
OH
Morphine
Ring numbering and nomenclature:

Based on phenanthrene thus these three rings are labeled A, B and C, other two are
labeled D and E

Morphinan (1946) refers to rings A, B, C and D of morphine, hence, epoxymorphinans
(more specifically the 4,5–α–epoxymorphinans)

Rings B and D of morphine is termed Morphan, Ring A is aromatic and, thus, flat, Ring C is
in the boat confirmation due to the double bond, Ring D is the nitrogen-containing piperidine
ring, Ring E is the ether or epoxide

5 chiral centers (5, 6, 9, 13, 14), hence, 25, or 32 stereoisomers (16 are possible due to
steric hindrance).

(–) Morphine is naturally produced, the absolute configuration was established in 1955 as
5R, 6S, 9R, 13S, 14R

The configuration at C9 is the most important, which determines the orientation and
distance between the protonated nitrogen and the phenyl ring. In most cases the more
active isomer is levorotatory. Usually the isomers with an S configuration are dextrorotatory
SARs of Epoxymorphinans
R1
N
10
1
A
2
3
R2
11
O
16
D14 R3
C 87
13
15
B
12
4
9
E
O
6
5
O
R4

Modifications of this class involve C3, C6, C7, C8, C14, and the piperidine
Nitrogen

The earliest molecular modifications were simple, such as esterification,
etherification, and increasing the length of the N–substituent

The net results were compounds with greater potency but also greater
toxicities and additional liabilities and side effects

Molecular modifications may be divided into three groups:

Ring “A”,

Ring “C”

Ring “D”
1. Ring “A” Modifications

A free phenolic OH is optimal for μ receptor (analgesia) affinity, but will decrease
LWPC and also leads to first pass glucuronidation leading to poorer oral
bioavailablity. Example: morphine

Conversion of the OH to ether causes decease in μ receptor affinity. Thus
codeine is a prodrug for its analgesic effect. The larger the group the slower this
proceeds and therefore, the larger the group the less μ receptor affinity

However, etherification increases antitussive effectiveness and do not need to
remove the alkyl group. This is probably through a different receptor

Etherification also increases LWPC. The larger the lipophilic substituent the
higher the LWPC and thus increased bioavailability and cannot glucuronidate.
Example: codeine
CH3
N
O
O
CH3
Codeine
OH
CH3



N
Conversion to an ester creates a prodrug which must be
hydrolyzed at C3 to interact with the receptor. For diacetyl
morphine (heroin) the ester at C6 does not have to be
removed for the receptor interaction. The C3 is more
susceptible to hydrolysis as phenyl is an electron
withdrawer
Such diacetyl derivative has increases LWPC and thus
enhanced penetration through the BBB and thus euphoric
rush which makes the compound more popular for abuse.
Example: heroin
Removal of ring E increases LWPC. So, in general, all
else being equal, a morphinan is overall more potent than
the corresponding epoxymorphinan. The ether bridge
does not interact with the receptor so does not affect μ
receptor affinity. Example: morphinans
O
O
O
O
O
H3C
CH3
Heroin
R1
N
1
2
R2
O
10 16 9
11
14
B15 D
12
A
3
13 C 8
5
7
4
6
Morphinans
R3
2. Ring C Modifications
CH3
N

Natural conformation of C6 Hydroxyl is α. In this conformation
it interacts, poorly, with a hydrophobic region of the receptor.
The interaction is not favorable since the hydroxyl is not
lipophilic. Addition of methyl group increases LWPC and μ
receptor affinity. Example: heterocodeine, a structural isomer
of codeine, which is more potent than even morphine
O
HO
O
H3C
Heterocodeine

Inversion to the β conformation increases μ receptor affinity as points away
from the lipophilic region so does not interact unfavorably

Removal of this OH increases μ receptor affinity it also removes unfavorable
interaction with the hydrophobic site
CH3
CH3
CH3
N
N
N
H lipophilic
HO
O
Morphi ne
H
site
OH
HO
O
H
Removal of C6 hydroxyl
OH
HO
O
H
Inversi on of C6

Oxidation decreases analgesic potency, which still possesses a polar oxygen,
and apparently interacts more unfavorably with the hydrophobic region on the
receptor

Replacing hydroxyl with methyl or methylene increases μ receptor affinity,
again, due to better hydrophobic interaction. Example: nalmefen. Introduction of
additional OH at C14 increases μ receptor affinity due to an increased hydrogen
bonding to an allosteric site

The C7, C8 (Δ7) olefinic bond saturation changes LWPC and μ receptor affinity.
Saturation gives a slight increase in LWPC and also ring “C” goes from boat to
chair conformation that changes the 3D position of C6 hydroxyl. This gets rid of
the unfavorable hydrophilic–hydrophobic interaction. Thus, this also increases μ
receptor affinity

Saturation plus oxidation of C6 oxygen produces an increase in μ receptor
affinity. The ketone is more rigid and held away from the hydrophobic region.
May even interact with an adjacent hydrophilic region
CH3
N
CH3
N
CH3
N
N
OH
HO
O
O
Oxi dat ion of of C6 hydroxyl
O
HO
pola r
site
O
HO
OH
Sat urat ion of 7
pola r
site
O
Sat urat ion of 7 and
oxi dati on of of C6 hydroxyl
HO
O
H2C
Nalmefene
R1

2N
Removal of ring C increases LWPC. Removed
C6 hydroxyl does not interact with the
hydrophobic site on the receptor unfavorably so it
increases μ receptor affinity. So, in general, all
else being equal, benzmorphans are more potent
than morphinans.
8 3
4'
3'
7
B 4C 9
A
2'
1
6
5
1'
HO
R2
R3
Benzmorphan
CH3
N

Introduction of ring F increases LWPC. All else
being equal, the oripavines are more potent than
the epoxymorphinans. Example: etorphine
H3C
CH3
OH
HO
O
O
H3C
Etorphine
3. Ring D Modifications

“R” configuration α to the N (C9) is optimal for μ receptor affinity

Removal of N-methyl decreases LWPC, Quaternization
decreases LWPC tremendously, N-oxide decreases LWPC
which is more polar through resonance where there is an N+
and O– form. What is the effect?

Increasing size of N-alkyl decreases μ receptor affinity through
steric hindrance but increases LWPC. As length of N-alkyl
increases, μ receptor affinity decreases. Until the chain is about
5 carbons (better if aralkyl) then μ receptor affinity starts to
increase slightly due to induced-dipole, induced-dipole
interaction with allosteric “A” site, which is a phenyl ring.



Branching, unsaturation or strained ring structures in the N-alkyl
substituent leads to antagonism or, at the very least, partial
agonism, for at least one of the opioid receptors. (Nalorphine,
Naltrexone)
N
OH
O
Methylnaltrexone (relistor, approved in Apr 2008) is a quaternized
compound which act peripherally as µ-opioid antagonist. Thus It has
been approved for treating (SC and oral) opioid drug induced
constipation without affecting analgesia or precipitating the
withdrawal syndromes of opioids.
Substituents that are 3 carbons in length have higher μ receptor
affinity as an antagonist than those with 4 carbons. Optimal
antagonistic potency is obtained when the N–substituent chain is 3
carbons in length. Includes allyl and methyl isopropyl groups.
Example: nalorphine
O
HO
Naltrexone
N+ CH3
OH
HO
O
O
Methylnaltrexone
CH2
N

At 5 carbons antagonism is lost and agonism returns due to
interaction with site “A”

Removal of C15 (breaking ring D) decreases μ receptor affinity
HO
O
Nalorphine
OH
Summarizing the Effects of altering chain length on N of
morphine structure
R
R = CH3
Morphine
= CH2CH3
= CH2CH2CH3
N
= CH2CH2CH2CH3
= (CH2)4CH3
HO
O
OH
= (CH2)5CH3
= CH3CH2
Agonist activity decreases
antagonist activity increases
No activity
Agonist activity increases
14x morphine
Morphinans
The morphinans were introduced in 1946. They are morphine without the
ether link but are produced synthetically. Numbering system is the same
as with morphine. Since these compounds are synthetic they are obtained
as racemates. The more potent isomer has an R configuration α to the
nitrogen (C9 is R)
R1
N
1
2
R2
O
10 16 9
11
14
B15 D
12
A
3
R3
13 C 8
5
7
4
6
Morphinans
Numbering system is similar to epoxymorphinans
SAR of Morphinans
Epoxymorphinans and morphinans interact with the receptor in a similar fashion and thus
exhibit similar pharmacological profiles and SARs especially in the C3 hydroxy, C14 hydroxy,
and the N–substituent. (–)–N–Methylmorphinan possess high degree of analgesic activity, i.e.,
the ether bridge is not necessary for activity, introduction of a phenolic OH increases potency



The racemic mixture is known as racemorphan and was marketed as
Dromoran™.
The levorotatory isomer with R configuration alpha to the nitrogen is
known as levorphanol. It is 6 to 8 times as potent an analgesic as
Morphine. It is also a potent antitussive. This high potency is due to (a) a
higher LWPC (1300 vs 8) (b) loss of the ether oxygen and the C6
hydroxyl (c) It also has higher receptor affinity. Advantages over
Morphine include better oral bioavailability and a longer duration of
action, but it has higher toxicities
CH3
N
HO
Levorphanol
CH3
The dextro isomer, dextrorphan is devoid of analgesic activity and
associated liabilities but remains a potent antitussive. It is further
substantiating the belief that analgesia and antitussive effect are
mediated through different receptors. The dextro isomer was O–
methylated to increase its antitussive potency which is marketed as
dextromethorphan. Dextromethorphan is said to be as potent as Codeine
as an antitussive without respiratory depression and associated side
effects
N
H
O
CH3
Dextromethorphan
CH2
CH2
N
N
>>
HO
HO
OH
Nalorphine
Levallorphan

O
The N–allyl derivative, levallorphan is a potent antagonist at μ receptors, five
times as potent as nalorphine
N
OH
HO
Butorphanol

Butorphanol has higher μ receptor affinity compared to morphine due to the
C14 hydroxyl but with little dependence liabilities and limited respiratory
depression. This drug is a mixed agonist/antagonist - κ agonist, μ antagonist.
Susceptible to significant first pass metabolism and administered parenterally
or intranasally. κ Agonists have lower ceiling analgesia effects and are not as
effective as μ agonist in severe pain.
Benzomorphans



R1
Introduced in the 1960s and are purely synthetic. Numbering
system changed
2N
8
In this series, the effects on the 2’ position and N–substituent
are the same as Morphine i.e., similar binding with receptor
Unlike previous classes the (+)–isomer retains significant
analgesic potency, but the (–)–isomers are still more potent
which have the “R” configuration at C1 (C α to N like
Morphine)
7
4'
B
A
3'
2'
3
6
1
4
5
1'
HO

R2 and R3, are essential for μ receptor affinity. R3 is down because the
piperidine ring is up but R2 may be up or down. The cis (R2 & R3) isomers
are called α and the trans isomers are called β. The α isomers are
superimposable on morphine, however, the β isomers have higher μ receptor
affinity than the α isomers. Still, α isomers have higher μ receptor affinity
compared to morphine (b > a > morphine)

Both α and β benzomorphans also have a higher LWPC than morphine
further adding to their overall potency. The β isomers have higher
dependence liabilities than α isomers. Therefore, clinically the weaker α
isomers are used.
C
9
R2
R3

Metazocine is the prototype. The LWPC is higher than
morphine

Cyclazocine (methylcyclopropyl) is a potent mixed
agonist/antagonist. High LWPC and high incidence of
hallucinations.


Phenazocine (a μ agonist marketed in Europe) is 14X more
potent than morphine due to phenethyl group interaction with
“A” site and due also to its increased lipophilicity
Ketazocine, not marketed in the US, has high affinity for the
κ receptor and gives the receptor its name
HO
N
CH3
HO
HO
CH3
HO
Metazocine
N
CH3
CH3
Phenazocine
CH3
N
CH3
CH3
Ketazocine
CH3
CH3
N
CH3
N
H
N
O
CH3
Cyclazocine
O
H
CH3
CH3
HO
Pentazocine
Pentazocine,
marketed in the US
m anta, k ago
Phenylpiperidines
R1



Meperidine is the prototype; potency about 20% of morphine
and higher LWPC. Short duration of action due to metabolism
of its ester and 40 - 60% bioavailable. About 1/3 as potent
orally as compared to parenteral
due to free rotation around the σ bond molecule is extremely
flexible. Unlike all previous rigid series (phenyl ring was axial
to the piperidine) the phenyl in this class moves to the less
energetic equatorial position (<0.1% of the molecules would
have a phenyl–axial conformation at any time, not enough to
account for its potency). This implies that it may bind to the
receptors in a different way than the rigid opioids, with
different SAR patterns. This also accounts for the low
receptor affinity and the lack of antitussive effect.
Meperidine is believed to bind with site “A” and the anionic
site “B”. Binding with site “A” is not as effective as binding to
site “D”
1N
2
6'
5'
4'
3
B5
1'
A
3'
6
4
R2
2'
R3
Phenylpiperidine
CH3
N
O
O
Meperidine
CH3
SAR of Phenylpiperidines

Removal or replacement of the phenyl with alkyl, aryl, or
aralkyl groups always decrease affinity for site “A”.

Separation of the phenyl and the ester groups decrease
potency. This modifications result in a change in the
distance between the nitrogen and the phenyl ring, a
critical feature. This decreases the ability to bind site “A”
and “B” simultaneously.


CH3
N
O
HO
Insertion of a meta hydroxyl does increase potency by
50%. Thus Bemidone has higher affinity for the “A” site
than meperidine possibly due to hydrogen bonding to an
adjacent site
Conversion of the ester to a ketone increases potency
and duration of action by increasing metabolic stability,
esters can be hydrolyzed but ketones cannot. Example:
ketobemidone
CH3
O
Bemidone
CH3
N
CH3
HO
O
Ketobemidone
Another molecular modification that stabilizes the molecule is reversal of the ester.
The Meperidine reverse ester (MPPP, N–methyl phenyl–4–propionoxy piperidine) has
a longer duration of action due to increased resistance to ester hydrolysis. However,
reversal of the ester group converts a stable group into a leaving group in vitro that
produce MPTP upon decomposition, which is converted to MPP+ by MAO–B
CH3
N
CH3
+
N
CH3
N
MAO– B
O C CH2CH3
O
CH3
N
O
CH3
O


Introduction of a methyl to MPPP at position 3 results in
stereoisomers having different potencies. The trans methyl
is called Alphaprodine and the cis isomer is Betaprodin.
Their respective potencies are 5 and 14 times Meperidine
In Alphaprodine the phenyl is axial while it is equatorial in
Betaprodine. This may account for the difference in potency.
The 3–methyl affects the conformation of the phenyl ring
with respect to the nitrogen decreasing μ receptor affinity
CH3
Alphaprodine
CH3
N
CH3
O
O
Betaprodine
CH3
SARs for the N–substituent

The SARs for the N–substituent are similar to epoxymorphinans.
Introduction of aralkyl substituents markedly increase potency

Expansion or contraction of the ring to seven or five members gives
compounds with analgesic activity but less μ receptor affinity due to a
change in relationship between the nitrogen and the phenyl ring
C
N


O
Diphenoxylate is highly lipophilic. However, in regular doses has
no CNS activity due to (a) highly protein bound and sequester in
the lipid bilayer, (b) rapidly hydrolyzed to the carboxylic acid
Diphenoxin which can not penetrate the blood brain barrier
Loperamide has high LWPC and also free of all CNS effects due
to high protein binding and twice as potent as Diphenoxylate.
Further, the high lipophilicity result in slow dissolution resulting in
slow absorption and 40% bioavailability. The lack of water
solubility prevents drug abuse because it can not be injected
CH3
O
Diphenoxylate
CH3
N
N
O
OH
Cl
N
Loperamide
CH3
Phenylpiperidine Type Antagonist

Alvimophan (Entereg) is the first phenyl piperidine
type µ-antagonist with limited CNS effect and thus
lower opioid drug induced side effects especially
constipation. It does not affect the analgesia
precipitate withdrawing syndrome. It got FDA
approval in May 2008. It binds the GI µ-receptor
strongly but dissociates slowly thus exhibiting
selective
peripheral
activity.
Thus
unlike
methylnaltrexone, which can not deliver into brain
due to positive charge, its selectivity is kinetically
controlled.
O
OH
O
NH
N
CH3
CH3
HO
Alvimophan
Anilidopiperidines
O
R1
1N
N
H
N1
4
piperidine
2
NH2
aniline
N
CH3
R3
N
O
6
3
O
N
CH3
5
4
O
N
H3 C
Anilidopiperidine
O
O
O
R2
N
CH3
Remif entanyl
N
CH3
Fentanyl

Moving the phenyl ring from direct attachment to the piperidine ring by one atom to
nitrogen on the side chain allows for the phenyl ring to assume the more favorable axial
conformation. Thus, the phenyl ring of the anilidopiperidines binds the “D” site similar to
the morphine “A” ring. 3-OH is not essential for binding to this site. This class includes
some of the most potent synthetic analgesics

Fentanyl: 50 to 100 times more potent than morphine. It has high μ receptor affinity
due to binding at “A”, “B” “C” and “D” sites. High LWPC and thus can be absorbed
through skin or oral mucosa. N at C4 and the alkyl through NCO bond increases μ
receptor affinity by correctly orienting the phenyl ring

Remifentanyl: Esters on N and at C4 lead to rapid inactivation by plasma esterases in
consistent with the soft drug / antedrug concept
Phenylpropylamines

The prototype is Methadone, can be viewed as a ring “D” opened
phenylpiperidines. When ring D of Morphine was opened there is a total loss of
activity but racemic Methadone is equal to Morphine in analgesic potency. Both
phenyl rings required for potency. Removal of one sharply reduces potency, may
help correct positioning of one phenyl with correct spacing to the protonated
amine for the anionic site

The phenyl ring of the phenylpropylamines binds the “D” site analogous to the
“A” ring of morphine rather than the “A” site as we saw with the
phenylpiperidines. They have high LWPC, low first pass due to metabolically
stable; it is not an ester but a ketone. Also has a long half-life
H 3C
N
CH3
R3
R4
R2
R1
Phenylpropylamine
SAR of Phenylpropylamines
N-substitution:

Generally the dimethylamino gives optimal potency. The diethylamino derivative is less
potent but 5 and 6 membered alicyclic basic units have comparable activity to the
dimethylamino group

The two carbon chain between the basic nitrogen and the quaternary carbon is the
optimal length

Removal of the 6–α–methyl (normethadone) decreases potency

Moving the 6 (a)-methyl to position 5 (β) gives Isomethadone which has 65% of the
potency

Ketone side chain is important for activity, removal or altering its length abolishes or
significantly decrease potency

Reduction of the ketone produces Methadol with decreased potency

All the above modifications result in changing the distance and orientation of
the basic amine and the phenyl group


Acetylating the alcohol produce a more potent analgesic
The levorotatory isomer is marketed as Levomethadyl acetate. A
single dose can suppress withdrawal for 3 days and is used in
rehabilitation programs. The levo isomer is 5 times more potent than
the dextro isomer
H 3C
Phenyl replaced
by a benzyl
CH3
Methyl has been
moved to the β
position
N
CH3
O
O
CH3
Ketone is replaced
by an ester
Propoxyphene
Potency decrease dramatically

The introduction of a benzyl creates a second chiral center with four possible isomers

The analgesic activity resides primarily in the (+) isomer with 2S,3R configuration. It
is marketed as Darvon™. It has 1/8 the potency of Methadone and 2/3 of Codeine.
Has lower addiction liabilities and toxicities

The (–) isomer with 2R,3S configuration was used as an antitussive called Novrad™
which lacks the classical opioid characteristics and a pure antitussive

The napsylate salt is used because it is water insoluble and is less likely to be
abused by injection
H3C
Tapentadol (Nucynta) is a simplified structure approved in
November 2008 as narcotic analgesic. It has a dual
mechanism of action as a µ-opioid agonist as well as a NE
reuptake inhibitor with analgesic potency comparable to
that of morphine with a more tolerable side effect profiles.
N
H3C
CH3
CH3
HO
Tapentadol
Oripavines
CH3
N
R1
N
10
1
11
A
2
3
HO
16
B 15 D
12 13
4
E
O
N
9
14
F
18 C
17
5
H3C
8
7
H3 C
R2
6
O
Oripavines
CH3
HO
O
O
H3C
CH3
CH3
CH3
OH
CH3
OH
HO
O
O
H3C
Etorphine
Buprinorphine

SAR is same as epoxymorphinans. Ring F introduces additional lipophilicity.
C7 attachments can increase LWPC. If they are large enough they may
begin to bind to site “A” and increase μ receptor affinity. This is especially
true if an aromatic ring such as a phenyl is attached

Buprenorphine, containing a large alkyl moiety, is 20-30 times more potent
than morphine, has a longer duration of action, does not produce severe
respiratory depression, and has low abuse potential

Etorphine is about 6000 times more potent than morphine, because it is 300
times more soluble in lipids and its affinity for opioid receptor is 20 times
stronger and its use is restricted to the capture of large animals
Case stories
Case 1. Late on Sunday afternoon, BC, a 26-year-old man, was playing softball
with is church team. While running to second base, BC was hit on the right side
of the face with a thrown ball, which resulted in a broken jaw in three places. He
was taken to the emergency room of a local hospital in considerable pain. An
oral surgeon was finally located at a party and asked to come to assess and
repair the damage. BC was administered an analgesic by injection while for the
oral surgeon. The oral surgeon wired BC’s jaw together, with restriction to a
liquid diet for 6 weeks; BC was then sent home.
CH2
CH3
N
N
N
OH
HO
O
CH3 O
N
CH3
O
OH
1
2
O
CH3
O
HO
3
Cl
N
4
O
1. Explain the four drugs shown (1-4) with regard to their suitability for
analgesia in this case. Rationalize your best choice and discuss why the
others were excluded.
Case 2. As a pharmacist specializing in home-health care, you are working with a
25-year-old terminal cancer patient, CB, who has recently moved to your city. For
pain management, she had previously been stabilized on structure 1 (4 mg q 4-6
h), but her new physician has written for another agent, 2.
CH3
N
N
1. What is the opioid receptor activity profile of each
OH
analgetic drawn?
2. What therapeutic advantages and disadvantages
O
HO
1
O
HO
O
2
O
would be realized with a switch to agent 2.
3. Would you fill this new prescription? Why, or why not?
4. Should you be worried about the possibility of opioid addiction in CB?
Study Guide
■ Structures and function of pro- and met-enkephalins
■ Different types of opioid receptors, their functions and
agonists/antagonists.
■ Drug-opioid receptor interactions
■ Different types of opioid analgesics with structures
■ SAR of epoxymorphinan. What happens if you etherify or esterify the
phenolic –OH and/or aliphatic –OH?
■ Know all about methylnaltrixone
■ Effect of altering chain length on N of morphine and related drugs.
■ Why morphinans are more potent than epoxymorphinans? (SAR)
■ How do you differentiate between oipiod agonist and antagonist from
the given structure?
■ Whicg phenylpiperidin derivatives are neurotoxic and which ones are
not? Why?
■ Why loparamide and diphenoxylate are not centrally active? What are
they used for?
Study Guide Cont.
■ Know all about Alvimophan (Entereg).
■ Different types of opioid receptors, their functions and
agonists/antagonists.
■ What are anilidopiperidine analgesics? Are they more or less potent
than morphine?
■ Structures and SAR of phenylpropylamine derivatives as narcotic
analgesics.
■ Which isomer of propoxyphen is analgesic and which one is antitussive?
■ Know all about dual acting Tapentadol (Nucynta)
■ Why oripavines are highly potent narcotic analgesics? What are they
mainly used for?