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Opioids

Dr. Majdi Bkhaitan

Department of Pharmaceutical Chemistry.

mmbakhaitan@uqu.edu.sa

www. http://medchem1432.pbworks.com

Clinical Significance

“Opioid agonists and partial agonist/antagonists generally act on δ, µ, and

κ receptors. All of these receptors have subtypes that provide varying

degrees of analgesia, euphoria or dysphoria, central nervous system

depression, and perhaps, the potential for tolerance. By modifying their

structures, proper ties can be changed to develop agents that require more

or less hepatic metabolism and, thus, affect the duration of action and the

bioavailability. Other changes in the chemical structures can yield agents

with much higher affinity for analgesic receptors, which corresponds to

more potency on a milligram-to-milligram basis. Other alterations of the

chemical structures can lead to improved profiles regarding respiratory

depression, emesis, tolerance, and allergenicity. By altering the affinities for

some receptors more than others, the addictive proper ties also may be

manipulated. Through an understanding of the relationship of chemical

structures to biological activity, the clinician can improve the select ion of

drug to the specific patient.”

Jill T. Johnson, Pharm.D., BCPS, Associate Professor

Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical

Sciences

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Analgesia/Analgesics • A number of classes of drugs that are used to relieve pain.

Are also called Anti-nociceptives:

• The non- steroidal anti-inflammatory agents have primarily a peripheral site of

action, are useful for mild to moderate pain, and often have an anti-inflammatory

effect associated with their pain-killing action.

• Local anesthetics inhibit pain transmission by inhibition of voltage- regulated

sodium channels. These agents often are highly toxic when used in

concentrations sufficient to relieve chronic or acute pain in ambulatory patients.

• Dissociative anesthetics (ketamine), and other compounds that act as inhibitors of

N-methyl -D-aspartate (NMDA)–activated glutamate receptors in the brain, are

effective antinociceptive agents when used alone or in combination with Opioids.

• Compounds, such as the anti-seizure drug Pregabulin, which inhibits voltage

regulated Ca2+ ion channels, are useful in treating neuropathic pain.

• Most central nervous system (CNS) depressants (e.g., ethanol, barbiturates, and

antipsychotics) will cause a decrease in pain perception

• Inhibitors of serotonin and nor epinephrine reuptake (i .e., antidepressant drugs)

are useful either alone and in combination with Opioids in treating certain cases

of chronic pain.

• Current research into the anti-nociceptive effects of centrally acting α-adrenergic,

cannabinoid, and nicotinic- receptor agonists may yield clinically useful

analgesics working by non-opioid mechanisms. Research in one or more of the

above areas may lead to new drugs, but at present, severe acute or chronic pain

generally is treated most effectively with opioid agents.

Opiates “opioids”

Until the 1980s, the term “Opiate” was used extensively to describe any natural or

synthetic agent that was derived from morphine. One could say an opiate was any

compound that was structurally related to morphine.

• In the mid-1970s, the discovery of peptides in the brain with pharmacological actions

similar to morphine prompted a change in nomenclature. The peptides were not easily

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related to morphine structurally, yet their actions were like those produced by morphine.

At this time, the term “Opioid” meaning opium- or morphine-like in terms of

pharmacological action, was introduced.

• The broad group of opium alkaloids, synthetic derivatives related to the opium alkaloids,

and the many naturally occurring and synthetic peptides with morphine- like

pharmacological effects and are antagonized by an Opioid antagonist, such as Naloxone

are called Opioids.

• Receptors to which opioid agents bind and initiate biological responses are called opioid

receptors.

• Opioid systems are responsible for a variety of processes in organisms, the best

characterized of which is analgesia.

• Classical opiate pharmacology derives largely from the isolation and characterization of

alkaloids (including morphine) of the opium poppy plant “Papaver somniferu”.

Definitions

Analgesia Absence of pain without loss of consciousness

Opioid receptor agonists Drugs with morphine-like effects that bind to

opiate receptors

Opioid receptor antagonists Drugs that bind to opiate receptors and

prevent/antagonize effects of opioid agonists

Mixed agonists/antagonists Drugs with agonist and antagonist effects at

different opiate receptors; used as analgesics

Endorphins

The opioid peptides isolated from mammalian tissue are known collectively as endorphins, a

word that is derived from a combination of “endogenous” and “morphine”. The opioid alkaloids

and all of the synthetic opioid derivatives are exogenous opioids; the endogenous opioids exert

their analgesic action at spinal and supraspinal sites. They also produce analgesia by a peripheral

mechanism of action associated with the inflammatory process. In the CNS, opioids exert an

inhibitory neurotransmitter or neuromodulator action on afferent pain-signaling neurons in the

dorsal horn of the spinal cord and on interconnecting neuronal pathways for pain signals within

the brain. In the brain, the arcuate nucleus, periaqueductal gray, and the thalamic areas are

especially rich in opioid receptors and are sites at which opioids exert an analgesic action. In the

spinal cord, concentrations of endogenous opioids are high in laminae 1, laminae 2, and

trigeminal nucleus areas. All of the endogenous opioid peptides and the three major classes of

opioid receptors appear to be at least partially involved in the modulation of pain. The

endogenous opioids exert their analgesic action at spinal and supraspinal sites, Analgesia that

results from acupuncture or is self- induced by a placebo or biofeedback mechanisms is caused by

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release of endogenous endorphins. Analgesia produced by these procedures can be prevented by

the previous dosage of a patient with an opioid antagonist.

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Endorphin Analogues: Analogues which are stable to peptidases and which would be orally

active. This can be achieved through Replacement of non-essential amino acids with unnatural

AA’s or D-AA’s to make enkephalin unrecognisable to peptidase enzymes.

Opioid Receptors

There are the three major types of opioid receptors: µ, κ, and δ

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Opioid Alkaloids

Opium contains numerous alkaloids (as Meconoate and sulfate salts) of which are therapeutically

most important:

• Morphine

• Codeine

• Noscapine

• Papaverine

• It also contains Thebaine that has convulsant properties.

In opium we can observe two types of basic structures:

• The phenanthrene type (as in morphine, codeine, thebaine)

• The benzylisoquoinoline type (as in Papaverine, Noscapine).

Biological effects of morphine:

• Increased tolerance to pain, Sleepy feeling, A sensation of

well-being, Lesser perception to external stimuli, Respiratory depression of

central origin, Tendency to cause addiction

N

CH3O

CH3O

CH2

OCH3

OCH3

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Neurobiology of Drug Abuse and Addiction The factors that drive some individuals to abuse drugs, with resultant tolerance and psychological

and physical dependence, remains unknown. It has been proposed that a deficiency exists in the

opioid-mediated self- reward system of individuals who have a predisposition to abuse addictive

drugs.

Self-Reward Response

It is now evident that all forms of drug addiction are driven by the stimulation of the brain's self-

reward system, which originates in the ventral tegmental nucleus (VTN) and extends to the

nucleus accumbens (NAC) area of the midbrain, The µ opioid agonists work upstream in the

reward neuronal system by exerting an inhibitory action on GABAergic neurons, thus removing

the inhibitory GABAergic tonus on DA neurons and initiating the self- reward response. The κ

opioid agonists work at a site more downstream in the system and cause the opposite effect of the

µ agonists. The κ neurons synapse directly onto the DA nerve terminal in the NAC and exert an

inhibitory effect (negative tonus) on DA release. Thus, a µ agonist will cause a self- reward and

euphoric stimulus, and a κ agonist will cause an aversive and dysphoric stimulus. Alcohol

(ethanol) also causes a stimulation of the self- reward system, partially, by acting on the µ opioid

neurons to facilitate the release of endogenous opioids Thus, the common driving pathway in

drug addiction is the euphoria experienced when a drug is taken and the self -reward system is

activated by DA release. The self- reward response tends to be self- limiting, because feedback

(adaptive) mechanisms in the nerve cells attenuate the reward delivered after prolonged or

repeated activation of the system. Highly abused substances tend to have high potency, full

efficacy, and a fast onset of action so that the reward signal is initiated and fully activated before

the adaptive process can take effect. Factors that contribute to fast onset of action are high

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lipophilicity of the drug and a dosing method that allows rapid distribution to the brain. Most

abused drugs are highly lipophilic so that they rapidly cross the blood-brain barrier. The dosage

routes preferred by drug addicts (smoking and intravenous injection) meet the criteria for fast

distribution to the brain.

Rehabilitation of Opioid Addiction The best-known treatment is the use of methadone maintenance in the rehabilitation of the opioid

addiction a well- run program, daily treatment with oral methadone maintains the addicted

(tolerant ) state while allowing minimal euphoric/aversive mood swings, attenuates drug craving,

decreases the spread of HIV (by decreasing needle sharing) , and minimizes the social destructive

behavior Other agents, such as the µ agonist L-α-acetylmethadol (levomethadyl ) and the partial µ

agonist buprenorphine, can be substituted for methadone and offer the advantage of dosing every

third day.

Evidence suggests that treatment of a detoxified opioid addict (i .e., an individual who has been

weaned from opioid dependence through a methadone or other treatment program) with a long-

acting opioid antagonist, such as naltrexone, can not only pharmacologically block readdiction

but also limit the addict 's drug-craving urge.

Morphine-like derivatives

First type of modifications brought about on morphine had the goal of separating the analgesic

effect from other types of side effects (side effects like addiction liability, respiratory depression,

GI disturbances, etc.)

These studies have focalized their attention upon modifying what are called “peripheral

groups”. Peripheral groups are:

1) Phenolic hydroxyl in position 3

2) Alcoholic

hydroxyl in

position 6.

3) Ether Bridge.

4) Alicyclic

unsaturated

linkage in position

7-8.

5) N-methyl group.

One of the more useful results in this stage was the synthesis of 5-methyl- dihydromorphinone.

This compound possesses addiction liability but it was found to be a very potent analgesic with a

minimum of other side effects like emesis and mental dullness. It was found that the methylation

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of the alicyclic ring and its reduction (or both changes) and the absence of the alcoholic group in

position 6 brings about more active compounds. The most active compounds are the 14-hydroxy

and the dihydrodeoxy derivatives, these latter represent the most active derivatives of this series.

Rigid Opioids

Morphinan Derivatives

• (N-methylmorphinans): these compounds differ from

the morphine nucleus in the lack of the ether bridge

between C4-C5. This suggests the unessential nature

of the ether bridge.

SAR

• The 3-hydroxy derivative of Morphinan (levorphanol)

(the structure above) is the analgesically active one,

and it exceeds in analgesic activity that of morphine for eight times; because of a

OH

N

CH3

1

2

3 4 5 6

7

8

910

11

12 13

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Opioids (Rigid & Non-Rigid)

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major μ opioid receptor affinity and because of its major lipophilicity which

allows higher concentrations to reach the brain.

• The dextrorotatory derivative possesses

antitussive activity as the 3-methoxy derivative

(Dextromethorphan).

• It is essential to observe the importance of the

phenolic OH in position 3, in fact the OH in

other positions produces inactive compounds.

• The N-allyl derivative (levallorphan) is a potent

morphine antagonist. Also the N-cycloprpylmethyl

derivative (cyclorphan) is an antagonist at μ receptors

but it acts as agonist at κ (Kappa) receptors (partial

agonist), prducing analgesia with less addiction but with

other unfortunate side effects like depression caused by

the dysphoria produced from the stimulation of κ

(Kappa) receptors and also hallucination.

• The N-aralalkyl derivatives are markedly (10-20 times) more active than their

parent compounds, they are represented by ethylphenyl, p-amino ethyl phenyl,

and ethyl furyl morphinans in an increasing potency order.

Benzomorphans “Benzazocines”

• These are derivatives lacking both the ether bridge and the alicyclic ring which is

replaced by one or two methyl groups.

SAR:

• The trimethyl derivatives are more active than the dimethyl ones.

• The N-phenyl ethyl derivative (Phenazocine) is almost 20 times more active than

the corresponding N-methyl compounds.

• It was possible in some of the derivatives of this series to divorce the analgesic

activity from the addictive one. This to demonstrate the possibility of separating

the

analgesic

activity

from

undesired

side

effects.

R3

R2

OH

N

R1

R1 = CH2CH2

R2= R3 = CH3

Phenazocine

R1= CH2CH=C(CH3)2

CH3= R3R2= Pentazocine

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• Partial antagonists with analgesic activity in the benzomorphan series were

prepared. The most prominent member is pentazocine and cyclozocine.

Pentazocine has antagonistic properties with much lower addiction liability than

morphine.

Metabolism of rigid opioids:

• Morphine is metabolized by conjugation

at the phenolic (OH). Metabolism occurs

in the liver, it occurs also in the

intestinal mucosa requiring the action of

sulfatransferase or glucuronidyl-

transferase enzymes.

• The 3-conjugates has low activity and

poor distribution. Conjugation at 6-OH

gives an active metabolite. Morphine is

also N-demethylated to nor-morphine,

which has decreased activity and

decreased bioavailability.

• Nor-Morphine undergoes N and O-

conjugation followed by excretion.

• Other rigid opioids (Morphinans,

Benzazocines) undergo similar routs of

metabolism of morphine. However

compounds with N-alkyl groups larger

than methyl get N-dealkylated as major

route of inactivation.

• Codeine in humans is 10% O-

demethylated to produce morphine that

plays an important role in its analgesic

effect

Non-Rigid Opioids

4-Phenyl Piperidine derivatives “Meperidine-like derivatives”

• Meperidine is a typical μ agonist with 1/5 of the activity of morphine.

Researchers who were trying to obtain an anti spasmodic agent discovered it

through the observation of typical side effect observed for morphine while testing

it upon test animals. It possesses an anti spasmodic activity but also analgesic,

morphine-like activity.

NCH3

R

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SAR

• Replacement of the N-methyl group with other aralalkyl groups brings about

much more potent derivatives as in pheneridine and aniliridine.

• Structural modification of the 4-phenylpiperidine has led to the discovery of 4-

anilido piperidine derivatives or the Fentanyl group that is 50 times more potent

than morphine and Lofentanyl which is 8400 folds more potent than morphine.

These agents are used usually as anesthesia adjuncts.

• On the other hand replacing the N-methyl group with a very bulky group

produces inactive compounds as in the case of diphenoxylate and loperamide

(Imodium®), however used in the treatment of diarrhea as OTC in the case of

Loperamide.

Metabolism

• Mepiridine is considered to have a relatively short duration of action. This is due

to a rapid first pass metabolism in the liver.

NCH2

CH2R

N C

O

C2H5

Fentanyl: R=H Lofentanyl R= -COOCH3

NCH2

CH2 OH

Cl

C

CON

CH3

CH3

Loperamide

NCH3

C

O

O C2H5

MFO

EstersaeNCH3

C

O

O H

NH

C

O

O C2H5

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• Methadone and Methadone-like derivatives • In this class of opioids we observe the disappearance of the piperidine ring; with

the tertiary amine group, in most of the members of this series, is acyclic. This to

demonstrate the unessential nature of a cyclic tertiary amine.

• Methadone, which is the principle element of this family, is twice as potent as

morphine, while its toxicity is three to ten times that of morphine, with high

addiction liability. It is used to alleviate pain and is also used to maintain addicts

in the rehabilitation of heroin addiction.

SAR:

• One of the most important derivatives of methadone is the acetyl prodrug of

Methadole, which is called L-α-acetylmethadol “LAAM”. This derivative is

characterized by longer duration of action than Methadone, due to its active

metabolites in vivo and the lack of the ketone group found in Methadone, which

is responsible for the relative rapid inactivation of it, in vivo. This allows a once

daily administration.

• R1 and R2 in all methadone

derivatives are represented by

phenyl rings.

• It is thought that one of the two

phenyl rings correspond to the

benzene found in all opioids.

Whilst the second is thought to

maintain the aliphatic chain in a

position relative to that of the

alicyclic ring found in morphine.

Therefore, any modification upon

these two phenyls will bring

about a decrease in activity.

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Tramadol.HCl

Represents a fragment of codeine’s structure, consisting of

the phenyl and cyclohexane rings, the drug possesses opioid

activity, although it is thought to be attributed to the O-

demethylated metabolite regarding the opioid fraction of

activity. It is demonstrated that Tramadol possesses NE and

5HT reuptake inhibitory activity. Tramadol has been used in

Europe since the 1980s and was introduced to the U.S.

market in 1995. The drug is non-addicting and, thus, is not a

scheduled agent. In addition, tramadol does not cause respiratory depression or constipation

Morphine antagonists

• An N-aliphatic group instead of the usual N-methyl group characterizes the SAR

of Morphine antagonists. Examples of the aliphatic groups encountered are N-

cyclopropylmethyl (CPM), N-cyclobutyl methyl (CBM), N-allyl and N-

secpentenyl group.

• Examples of morphine derivative antagonists we can mention Naloxone,

naltrexone (considered as pure antagonists) Nalorphine and Nalbufine

(considered as partial antagonists )

• Examples of Morphinan derivative antagonists: we mention Levallorphan (as pure

antagonist),

cyclorphan and

Butorphanol

(considered partial

antagonists).

OOH

N

OH

CH2

OOH

N

OH

O

R

CH2 R=

R= CH2CH=CH2

Naltroxone

Naloxone

Nalbufine

OH

N

R

R= CH2

R= CH2

(Cyclorphan)

(Butorphanol)

R= CH2CH=CH2 (Levallorphan)

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• Example of benzomorphan antagonists we can mention Pentazocine (considered as

partial antagonist).

Clinical uses of antagonists

Pure antagonists

• Are used as antidotes in overdose, they have the ability to reverse the respiratory

depression and deprive addicts from the euphorogenic effect of Heroine.

Some pure antagonists like Naloxone and more importantly Naltrexone are used in the

treatment of addiction in addicts.

Diagnostic test to determine narcotic addiction.

Partial antagonists:

Such as butorphanol and Pentazocine are used as:

True analgesics with less addiction liability with respect to pure agonists

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μ receptor Binding Theories

1) Becket and Casey theory

2) Bimodal Binding Model theory

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3) Enkephalin binding mode based theory

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Antitussive agents • Cough is a protective, physiologic reflex that occurs in health as well as in

disease. Among the agents used in the symptomatic control of cough are those

that act by depressing the cough center located in the medulla. These have been

called anodynes, cough suppressants, and centrally acting antitussives. Until

recently, the only effective drugs in this area were members of the narcotic

analgesic agents.

• The more important and widely used ones were Morphine, hydromorphone,

codeine, hydrocodone, methadone, and levorphanol.

• In recent years, several compounds have been synthesized that possess

antitussive activity without the addiction liability of the narcotic agents. Some of

these new agents act in a similar manner through a central effect. It is suggested

that a bronchodilation is essential in cough relief.

• In addition to the primary antitussive agent. The more important ones include

antihistamines, sympathomimetics (bronchodilators) as ephedrine, phenylpropanolamine,

parasympatholytics and expectorants.

Codeine

• It occurs naturally, but is also produced in major quantities from morphine or even thebaine. It

is less effective orally than parenterally. It has one-tenth the potency of morphine as analgesic

due to the methylation of the phenolic hydroxyl. In high doses it can cause the same side

effects of morphine “respiratory depression, constipation, nausea, and such”. Codeine has the

reputation of being antitussive, depressing the cough reflex, and is used in many cough

preparations.

Dextromethorphan

• This drug is the O-methylated (+) form of racemorphan remaining after the resolution

necessary in the preparation of levorphanol. It possesses the antitussive properties of Codeine,

without the analgesic, addictive, central depressant, and constipating features. 10 mg are

suggested as being equivalent to 15mg of codeine as antitussive agent. This product has

replaced codeine and other older antitussive agents.

• Other antitussive agents are Noscapine, Benzonatate, Caramiphen, and carbetapentene.

References:

Foy’s: Principles of Medicinal Chemistry, Opioid Analgesics,Sixth edition,

David S. Fries, Chapter 24