Opioids

Opium poppy capsule (Papaver somniferum), the source of both opium and the poppy seeds you find on bread

Namut Ali inhales heroin in a cemetery near Quetta. Heroin coming across the Afghan border to Pakistan costs only about $1 a gram. (By Adrees Latif, Reuters)

Opium poppy cultivation

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)

12

N

Morphine

HO OH

N

O

CH3

Papaverine

N

OCH3

OCH3

OH3C

OH3C

CH3

HO

N

Levorphanol

CH2

HO

N

Levallorphan

CH2

HO

OH

O

N

O

Naloxone

CH3

CH3

HO

N

Phenazocine

HO OH

N

O

CH3

Morphine (1925)

Codeine (1929)

O OH

N

O

CH3

CH3

HO OH

N

O

Nolorphine (1941)

N

CH3

CH3O

CH3

O

Alphaprodine (1946)

NNH3C

OFentanyl (1964)

(1946)

(1951)

(1963)

(1959)

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

H2N-Tyr-Gly-Gly-Phe-Leu-COOHLeu-enkephalin

NH

HN

NH

HONH2

O

O

O

HN

OHO

O

H2N-Tyr-Gly-Gly-Phe-Met-COOHMet-enkephalin

NH

HN

NH

HONH2

O

O

O

HN

OHO

O

S

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 “C” is a cavity that accomodates C15 of morphine

Site “B” is an anionic site that binds the protonated nitrogen of the pyridine ring (ring “D”) found in 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

Ring Nomenclature and Numbering

Epoximorphinan

N

R1

O R4OOR2

R3

A

E

B D

C

1

2

3 4 56

78

14

910

11

1213

15

16

Morphinan

N

R1

OR2

R3

A

B D

C

1

2

3 45

6

7

8

14

910

11

1213

15

16

Benzmorphan

R3R2

N

R1

HO

A

B C

1

2

3

4

56

7

8

4' 9

3'

2'1'

Phenylpiperidine

R2

N

R1

R3

A

B

1

2

3

4

5

6

5' 6'

4'

3' 2'

1'

Anilopiperidine

1

2

3

4

5

6

N

R1

NR3

R2

Phenylpropylamine

N

R1

R2

H3C

CH3

R3

R4Oripavines

HO O

1

212

10

11

4 5

9

18

16

15

6

14

13 173

N

O

R1

CH3

A

BC

D

E

8

7F R2

Removal of ring E

Removal of ring C

Removal of ring B

Removal of ring D

Adding a ring F

Epoxymorphinans

O O

1

212

10

11

4 5

9

8

16

15

6

14

13 73

N

O

R1

R2 R4

A

B

C

D

E

R3

HO OH

N

O

CH3

General structure 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

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”

O O

1

212

10

11

4 5

9

8

16

15

6

14

13 73

N

O

R1

R2 R4

A

B

C

D

E

R3

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

O

N

CH3

O OH

CH3

Codeine

O

H3C

O

CH3

O

CH3

O

N

O

Heroin

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 Morphinans

N

R1

OR2

R3

A

B D

C

1

2

3 45

6

7

8

14

910

11

1213

15

16

2. Ring C Modifications

H3C

HO

CH3

O

N

O

Heterocodeine O

N

CH3

OHHO

H

O

N

CH3

HHO

OH

O

N

CH3

HHO

H

Morphine Inversion of C6Removal of C6 hydroxyl

lipophilicsite

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

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

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

HO

OH

H2C

N

O

Nalmefene

polarsite

O

N

O

CH3

HOO

N

CH3

HOO

Oxidation of of C6 hydroxylSaturation of 7 Saturation of 7 and

oxidation of of C6 hydroxyl

O

N

OH

CH3

HO

polarsite

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.

Introduction of ring F increases LWPC. All else being equal, the oripavines are more potent than the epoxymorphinans. Example: etorphine

Benzmorphan

R3R2

N

R1

HO

A

B C

1

2

3

4

56

7

8

4' 9

3'

2'1'

HO

CH3

OH

H3C

CH3

O

N

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)

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

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

CH2

O

N

OHHO

Nalorphine

HO

OH

O

N

O

Naltrexone

HO

OH

O

N+

O

Methylnaltrexone

CH3

HO OH

N

O

R= CH2CH3

= CH2CH2CH3

= CH2CH2CH2CH3

= (CH2)4CH3

= (CH2)5CH3

= CH3CH2

R = CH3 MorphineAgonist activity decreasesantagonist activity increases

No activity

Agonist activity increases

14x morphine

Summarizing the Effects of altering chain length on N of morphine structure

Morphinans

Morphinans

N

R1

OR2

R3

A

B D

C

1

2

3 45

6

7

8

14

910

11

1213

15

16

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)

Numbering system is similar to epoxymorphinans

SAR of Morphinans

CH3

HO

N

Levorphanol

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

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

H

CH3

O

CH3

N

Dextromethorphan

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.

The N–allyl derivative, levallorphan is a potent antagonist at μ receptors, five times as potent as nalorphine

CH2

O

N

OHHO

Nalorphine

CH2

HO

N

Levallorphan

>>

OH

HO

N

Butorphanol

Benzomorphans

AB C

2' 1'

6

74'

3'

18

N2

4

3

R25

9

R3

HO

R1 Introduced in the 1960s and are purely synthetic. Numbering system changed

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)

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 ( > > 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.

HN

OH

CH3

CH3

HO

N

Cyclazocine

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

CH3

CH3

CH3

HO

N

Metazocine

CH3

CH3

HO

N

Phenazocine

CH3

CH3

HO

NO

Ketazocine

CH3

CH3

CH3

CH3

HO

N

Pentazocine

Pentazocine, marketed in the US

anta, ago

Phenylpiperidines

Phenylpiperidine

R2

N

R1

R3

A

B

1

2

3

4

5

6

5' 6'

4'

3' 2'

1'

O

N

CH3

CH3O

Meperidine

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”

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.

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

HO O

N

CH3

CH3O

Bemidone

HO O

N

CH3

CH3

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

N

O C

O

CH2CH3

CH3

N

CH3

N

CH3+

MAO–B

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

CH3O

N

CH3

CH3O

Alphaprodine

CH3

O

N

CH3

CH3O

Betaprodine

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

SARs for the N–substituent

C

O

N

CH3O

N

Diphenoxylate

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

O CH3

CH3N

Cl

N

OH

Loperamide

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.

Phenylpiperidine Type Antagonist

HO

N

CH3

Alvimophan

CH3

O NH

O

OH

Anilidopiperidines NH2

piperidine aniline

HN 1

4

N

N

CH3

OO

CH3

N

N

Fentanyl

O

O

CH3O

H3C O N

N

CH3

O

Remif entanyl

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

Anilidopiperidine

1

2

3

4

5

6N

R1

NR3

R2

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

Phenylpropylamine

N

R1

R2

H3C

CH3

R3

R4

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 ()-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

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

NCH3H3C

CH3

O

CH3O

Propoxyphene

Ketone is replaced by an ester

Phenyl replaced by a benzyl

Methyl has been moved to the β position

Potency decrease dramatically

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

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.

Tapentadol

N

H3C

CH3

HO

CH3H3C

Oripavines

HO O

1

212

10

11

4 5

9

18

16

15

6

14

13 173

N

O

R1

CH3

A

BC

D

E

8

7F R2

Oripavines HO O

N

O

CH3

CH3

CH3

OH

H3C

H3CBuprinorphine

HO

CH3

OH

H3C

CH3

O

N

O

H3C

Etorphine

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 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.

HO OH

N

O

CH3

1 O

N

CH3

CH3O

2

CH2

HO

OH

O

N

O

3

CH3

Cl

O

N

N

4

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 stories

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.

HO

CH3

O

N

O

1HO

OH

O

N

O

2

1. What is the opioid receptor activity profile of each analgetic drawn?

2. What therapeutic advantages and disadvantages 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?