Narcotic Analgesics (OPIOID ANALGESICS), SAR of Morphine, Narcotic antagonist – Medicinal Chemistry

Narcotic Analgesics (OPIOID ANALGESICS)

Learning Outcomes

At the end of the
lecture, student will be able to

• Write on narcotic analgesics

• Chart the history of narcotic analgesics

• Recall the opioid receptors

• Classify the narcotic analgesics

• Recognize the specific uses of the narcotic analgesics

• Discuss the side effects of narcotic analgesics

• Understand the SAR of Morphine

• Describe the peripheral and nuclear modifications done to
the morphine ring and its effect on the activity

• Summarize about narcotic antagonists and their uses


• Narcotic analgesics

• The history of narcotic analgesics

• The opioid receptors

• Classify the narcotic analgesics

• The specific uses of the narcotic analgesics

• The side effects of narcotic analgesics

• The SAR of Morphine

• The peripheral and nuclear modifications done to the
morphine ring and its effect on the activity

• Narcotic antagonists and their uses


• Narcotic analgesics are drugs that relieve pain, can cause
numbness and induce a state of unconsciousness.

• They work by binding to opioid receptor, which are present
in the central and peripheral nervous system

• Narcosis: a
state of stupor, drowsiness, or unconsciousness produced by drugs.

• Stupor:
impaired consciousness with decreased reactivity to environmental stimulli


• Opium was known to man many centuries ago

• This is evident from the Ebers Papyrus and Homer’s
Odyessey where the use of opium was mentioned

• Opium is obtained by making superficial incisions on the
immature and unripe capsules of Papaver somniferum (or poppy plant)

• The exudate is air-dried and then powdered to give the
official powdered opium

• A systematic study of the plant material led to the
isolation and identification of the most important alkaloid known as morphine
in 1803

• Other alkaloids isolated from opium include codeine,
papaverine and thebaine

• The opium class of narcotic drugs are considered not only
as the most potent and clinically useful agents causing depression of central
nervous system, but also as very strong analgesics

• Morphine and morphine-like drugs are referred to as
opioids or opiates. They are also known as narcotic analgesics

• ‘narcotic’ is derived from the Greek word ‘narcotic’
meaning drowsiness

• The term narcotic is now used to refer to dependence
producing drugs

Historical perspective of Narcotic Analgesics

• First undisputed reference to “poppy juice” is
found in the writings of Theophrastus in the third century B.C.

• The word opium being derived from the Greek word for

• The drug being obtained from the juice of the poppy
Papaver sominiferum

• Arabian physicians were well versed in its uses and
introduced the plant to the Orient

• Paracelsus, circa 1500, is credited with repopularising
the drug in Europe, where it had fallen out of favor due to toxicity

• In the 18th century opium smoking became popular in the
Orient and its ready availability in Europe led to considerable abuse

• Opium contains more than 20 alkaloids

• Morphine was first isolated by Friedrich Sertürner-1804

• He originally named it morphium after the Greek god of
dreams, Morpheus.

• Isolation of other alkaloids soon followed, codeine in
1832 and papaverine in 1848

• By the middle of the 19th century, use of the pure
alkaloids rather than crude opium was becoming widespread

 • The problems of
widespread addiction led to the search for a morphine antagonist, and in 1951 nalorphine
was used in the RX of morphine overdose

• At the same time, the analgesic effects stimulated the
development of  a number of new
drugs, including naloxone, pentazocine, butorphanol etc.

• By 1967, researchers had concluded that the complex
interactions and differences between morphine and its derivatives could only be
explained by the existence of more than one receptor type ® receptor dualism,
Martin (1967)

• In 1973, following an approach developed by Goldstein, 3
groups of workers described saturable, stereospecific binding sites for opiate

• Modifications of the morphine molecule are considered
under the following headings:

• Early changes on morphine before Small, Eddy and their

• Changes on morphine initiated in 1929 by Small, Eddy and

• By- Eisleb and Schaumann in 1938 – discovery of potent
analgesic meperidine (pethidine).

• By Grewe in 1946- synthesis of the morphinan group of


 • Work by binding to
opioid receptors, in the CNS, PNS and GIT

– Receptors mediate the beneficial, psychoactive effects and
side effects

• Opiate – often used as a synonym for opioid- but the term
opiate is limited to the natural alkaloids found in the resin of the opium

• While opioid refers to both opiates and synthetic
substances, as well as to opioid peptides

Opioid Site of action


Delta (δ) – Brain
(pontine nuclei, amygdala, olfactory bulbs, deep cortex) & peripheral
sensory neurons

Kappa (κ) – Brain
(Hypothalamus), Spinal cord & peripheral sensory neurons

Mu (μ) – Brain
(Cortex, thalamus), Spinal cord, intestinal tract & peripheral sensory

Opioid Receptors

effects of 



• Constipation

• Nausea

• Dizziness

• Head ache

• Dry mouth


• Respiratory depression

• Chest pain

• Abnormal heart beat

Classification of narcotic ligands

A) Narcotic

I. Natural Alkaloids
of Opium

• Phenanthrenes: morphine, codeine, thebaine

• Benzylisoquinolines: papaverine, noscapine

II. Semi-synthetic

• Diacetylmorphine (heroin), hydromorphone, oxymorphone
hydrocodone, oxycodone

III. Synthetic

• Phenylpiperidines: pethidine, fentanyl, alfentanyl,

• Benzmorphans: pentazocine, phenazocine, cyclazocine

• Propionanilides: methadone

• Morphinans: levorphanol

B) Mixed
agonist-antagonist drugs
(eg, nalbuphine, pentazocine) have agonist
activity at some receptors and antagonist activity at other receptors; also
included are the partial agonists (eg, butorphanol, buprenorphine).

C) Narcotic
Narcotic antagonists (eg, naloxone) do not have agonist
activity at any of the opioid receptor sites. Antagonists block the opiate
receptor, inhibit pharmacological activity of the agonist, and precipitate
withdrawal in dependent patients.

The narcotic analgesics are usually classified on the basis
of their basic chemical structures as discussed below along with a few
classical examples from each category.

Sulphate BAN, Morphine Sulfate USAN.

Morphine Sulphate

• Obtained from unriped capsule of papaver somniferum

• Odourless, laevorotatory, white needle like crystals –
bitter taste

• It is employed extensively as an analgesic, antitussive,
adjunct to anaesthesia and nonspecific antidiarrheal agent.

• In small doses it helps to alleviate continued dull pain,
whereas in large doses to relieve acute pain of traumatic or visceral origin



• Levorotatory, colourless & efflorescent crystals

• Not used as narcotic analgesic- has slight analgesic

• Used in the treatment of cough

• Codeine phosphate and Codeine Sulphate 10–20 mg/dose

Hydrochloride BAN, USAN, Anileridine INN

Anileridine Hydrochloride

• It is a narcotic analgesic, having related chemical
structure to that of pethidine

• Anileridine is more active than merperidine and has the
same uses and limitations

• But with longer duration



• Chemically it is

• Loperamide is synthetic opioid that primarily affects
opiate receptors in the intestine and is used to treat diarrheal

• One of the long-acting synthetic ANTIDIARRHEALS

Citrate BAN, USAN, Fentanyl INN,: Durogesic

Fentanyl Citrate

• It is a white or almost white powder soluble in water,
freely soluble in methanol, and sparingly soluble in alcohol.

• Fentanyl is related to pethidine and also to basic
anilides with analgesic properties and is characterized by high potency, rapid
onset, and short duration of action.

• A potent narcotic analgesic employed for the arrest of

• It may also be employed as an adjuvant for all such drugs
mostly used for regional and general anaesthesia


Fentanyl Citrate Synthesis

Hydrochloride BAN, USAN, Methadone INN,

• It is a Phenylpropylamine Analogues

• It is a potent narcotic analgesics having actions
quantitatively comparable to morphine though slightly less potent than morphine
as an analgesic. Besides, it exerts sedation and antitussive properties

• Similar actions to morphine-Longer duration of action

Methadone Hydrochloride BAN, USAN, Methadone INN,

• Less problems with withdrawal.

– Can be used to wean heroin and morphine addicts off the

– reduces withdrawal symptoms in people addicted to heroin

It is a white or almost white crystalline powder, freely
soluble in ethanol and soluble in water.

Methadone Hydrochloride Synthesis

Hydrochloride BAN, Propoxyphene Hydrochloride USAN, Dextropropoxyphene INN,

Dextropropoxyphene Hydrochloride

• Dextropropoxyphene is a narcotic analgesic possessing
relatively milder actions and bearing structural resemblance to methadone.

• It is a white or almost white crystalline powder, very
soluble in water and freely soluble in alcohol.

• It is usually used to control mild to moderate pain and

• used along with other analgesics having anti-inflammatory
and antipyertic properties like paracetamol and aspirin.


Pentazocine INN, BAN, USAN

• It is a synthetic analgesic agent commonly used for the
control of moderate to acute pain.

• It exerts some sedative actions.

• It causes incomplete reversal of the respiratory,
cardiovascular and behavioural depression produced by either meperidine or

• It behaves both as an agonist and as an antagonist.

• It is reported to be 3 to 4 times less potent than
morphine and about 50 times less potent than nalorphine.

• It is a white or almost white powder sparingly soluble in
water, soluble in ethanol, and sparingly soluble in methylene chloride

Tartrate BAN, USAN, INN.

Levorphanol Tartrate

• It exists as white, odourless, crystalline powder, soluble
in water and alcohol, insoluble in chloroform and ether.

• It is a potent narcotic analgesic having actions and
structure similar to that of morphine.

• It is used effectively for the management of both moderate

SAR of

SAR of Morphine was studied by

1. Modification of alicyclic ring

2. Modification of aromatic ring

3. Modification of 3o Nitrogen

SAR of Morphine

A. Morphine Structure
and Chemistry

• The prototypic narcotic analgesic is (-)-morphine, the
principal alkaloid obtained from the opium poppy (Papaver somniferum).

• Because of its natural source, morphine and morphine
derivatives are referred to as opiates.

• Narcotic analgesics will be classified on the basis of
their structural derivation from morphine

Morphine Structure and Chemistry

1. A rigid pentacyclic structure consisting of a benzene
ring (A), two partially unsaturated cyclohexane rings (B and C), a piperidine
ring (D) and a dihydrofuran ring (E).

Rings A, B and C are the phenanthrene ring system. This ring
system has little conformational flexibility (the importance of this will be
addressed later).

2. Two hydroxyl functional groups, a C3-phenolic OH (pKa
9.9) and a C6- allylic OH

3. An ether linkage between C4 and C5,

4. Unsaturation between C7 and C8,

5. A basic, 3o-amine function at position 17,

6. 5 centers of chirality (C5, C6, C9, C13 and C14) with
morphine exhibiting a high degree of stereoselectivity of analgesic action.
Only (-)-morphine is active!

• Morphine contains both an acidic phenolic group and a
basic tertiary amine functions.

• However,since the amine functions is significantly more
basic than phenol group is acidic, thus, morphine as well as a majority of
narcotic analgesics are functionally basic compounds both pharmaceutically (dosage
forms) and physiologically.

• Hence, morphine exists as a cation at physiologic pH, and
readily forms salts with appropriate acids (commercial products are sulfate and

Morphine Structure and Chemistry


• Limited oral bioavailability due to extensive first pass
metabolism (see below)

• Lipophilic, but less so than other opioids (i.e. heroin)

• Half-life: 2-3 hrs: Metabolism

• Elimination: Primarily in urine as the glucuronide

• Metabolism: 3- and 6-O-glucuronides, OND and O-methylation
to codeine (minor)

Morphine Biodisposition/Metabolism

III. “Peripherally
Modified Morphines”: Ring A Analogues

• Ring A and its 3-hydroxyl group is an important structural
feature for analgesic activity

• Removal of the 3-OH group reduces analgesic activity

Peripherally Modified Morphines

• Altering the C-3 OH by etherification as shown by the
derivatives below reduces narcotic analgesic activity, the larger the ether
group, the lower the analgesic activity.

• While less active as analgesics, compounds such as codeine
possess very useful antitussive activity.

Peripherally Modified Morphines

• Esterification (acetylation) of both the 3- and 6-OH
groups yields heroin, a compound which is both more lipophilic and more potent

• The primary factor involved in increased analgesic potency
is the increased lipophilicity and distribution to the CNS.

Peripherally Modified Morphines

IV. “Peripherally
Modified Morphines”: Ring C Analogues

• The 6-OH of morphine are not required for analgesic
activity as indicated by the relative potencies of the following morphine analogues.

• Elimination of the 6-OH actually enhances activity.

• Etherification of this group with relatively small alkyl
group also increases activity.

• Esterification of the 6-OH as in the main hydrolysis
metabolite of heroin, 6-MAM, also increases analgesic activity.

• This increased activity appears to result largely from the
enhanced lipophilicity of these compounds and their increased ability to penetrate
the CNS.

Peripherally Modified Morphines

• The 7,8-double bond of morphine also is not required for
analgesic activity as indicated by the relative analgesic potency of

• Also, oxidation of the 6-OH of dihydromorphine to yield hydromorphone
further increases activity.

• And substitution of a 14-OH group on the hydromorphone
structure as in oxymorphone produces a further increase in analgesic activity
(RP= 10).

• Oxidation of the 6-OH of morphine directly as in morphone
(without reduction of the 7,8-double bond) does not significantly alter
analgesic activity.

Peripherally Modified Morphines

V. “Peripherally
Modified Morphines”: Ring E Analogues

• Simple ring-opened analogues of morphine such as the
compound below are less active.

• However, a number of morphine analogues in which this ring
and its functionality are completed removed retain high analgesic activity.

Peripherally Modified Morphines

VI. “Peripherally
Modified Morphines”: Ring D Analogues and the Tertiary Amine Function

• Replacement of morphine’s N-methyl group by a hydrogen
atom as in normorphine reduces analgesic activity to 1/8th that of morphine.
Much of this decrease is due to increased polarity resulting in reduced BBB translocation
to the CNS.

• The quaternary methiodide analogue of morphine is inactive
when administered peripherally (by injection) but equi-active when administered
directly into the CNS.

• The activity of this compound demonstrates the importance
of cationic structure of morphine for morphine, and the role of structure in
CNS penetration

Peripherally Modified Morphines

• Replacement of morphine’s N-methyl group with larger alkyl
groups reduces activity.

• However, substitution with aralkyl groups significantly
increases analgesic activity as illustrated by Nphenethylnormorphine

Peripherally Modified Morphines

• Replacement of morphine’s N-methyl group with an allyl
group (-CH2-CH=CH2), amethylcyclopropyl group or a methylcyclobutyl group results
in the emergence of opiate receptor antagonist activity

Peripherally Modified Morphines

• Replacement of the potent narcotic agonist oxymorphone’s
N-methyl group with an allyl group (-CH2-CH=CH2), a methylcyclopropyl group or
a methylcyclobutyl group also results in the emergence of opiate receptor
antagonist activity

• Three of these compounds – naloxone HC1 (Narcan)
naltrexone HCl (Trexan) and nalmefene (Revex) -are pure opiate antagonists (at
mu, kappa and delta receptors) and

• are used for the reversal of the narcotic/respiratory
depression induced by opiate agonists, as well as psychotomimetic actions.

• These compounds are also used as adjuncts to the
maintenance of an opiate-free state in detoxified, formerly opiate-dependent

Peripherally Modified Morphines

VII. “Peripherally
Modified Morphines”: The Thebaines

Annelation – adding a sixth ring across carbons 6 and 14 of
the C ring of morphine – yields thebaine compounds such as etorphine which are
extremely potent analgesics.

These compounds as typically used to immobilize large
animals (elephants).

Nuclear modification

• At C2, if it is NH2, decreases NAA

• At C1, if it is halogens, decreases NAA

• Dihydromorphinone, at C14, if it is –OH, increases NAA

• Dihydrocodeinone, at C14, if it is –OH, increases NAA

• Instead of –OH, if it is -CH3 at C6 increases the activity

• If it is saturated, it has lesser activity, ex: synthetic

SAR of Morphine

Summarised SAR of Morphine


• An antagonist used to counteract the effects of narcotics
(especially to counteract the depression of respiration)

• Narcotic antagonists: Prevents or abolishes excessive
respiratory depression caused by the administration of morphine or related

• They act by competing for the same analgesic receptor

• They are structurally related to morphine with the
exception of the group attached to nitrogen

Narcotic antagonist

Classification of 

Narcotic antagonist

i. Pure antagonists
(e.g. naloxone, naltrexone).

ii. Partial agonists
of nalorphine type
(e.g. Nalorphine, levallorphan, and cyclazocine).

iii. Partial agonists
of morphine type
(e.g. propiram, profadol).

Classification of Narcotic antagonist

Hydrochloride BAN, USAN, Nalorphine INN,

Nalorphine Hydrochloride BAN, USAN, Nalorphine INN,

• It is a narcotic antagonist having certain agonist actions
that reduce the depressant actions particularly of morphine together with other
narcotic drugs

   Used as diagnostic
agent to detect Morphine addiction

– It precipitates the withdrawal symptoms in patients
addicted to Heroine & Methadone

• Decreases the drug dependence when administered along with

• It has little antagonist effect towards barbiturate or
general anaesthetic depression

• However, it has strong analgesic properties, but it is not
acceptable for such use owing to the high incidence of undesirable psychotic

• It is effectively employed to reverse narcotic-induced
respiratory depression

Hydrochloride BAN, USAN, Naloxone INN

Naloxone Hydrochloride BAN, USAN, Naloxone INN

• It is almost seven times more active than nalorphine in
antagonizing the effects of morphine.

• It shows no withdrawal effects after long-term

• It lacks not only the analgesic activity shown by other
antagonists, but also all of the other agonist effects.

• At higher doses, Naloxone may be useful in the treatment
of shock 



• Pure opioid antagonist.

• μ, κ and δ-antagonist.

• No concomitant agonist properties.

• Naloxone- to counter the effects of opioid overdose, such
as heroin or morphine in the life-threatening depression of the CNS,
respiratory system, and hypotension.



• Opioid receptor antagonist.

• μ, κ and δ-antagonist.

• Used in the management of alcohol and opioid dependence.



• Levallorphan resembles nalorphine in its pharmacological
action and is about five times more effective as a narcotic antagonist.

• It is useful in combination with analgesics, such as
meperidine, alphaprodine, and levorphanol to prevent the respiratory depression
usually associated with these drugs.


• Morphine was isolated in 1804

• Synthetic derivatives were prepared only a century later

• The opoid receptors are Mu, kappa and delta

• The narcotic analgesics are classified as

– Naturally occurring opium alkaloids: Morphine, Codeine

– Semi-synthetic opium derivatives:Heroin ,Oxymorphone

– Synthetic morphine substitutes: Pethidine,Levorphanol,

– Miscellaneous: Pentazocine

• Narcotic analgesics are used in chronic pain

• Most of the narcotic analgesics are habit forming

• Morphine is taken as reference to compare the SAR of
modified substances. Its NAA (Narcotic analgesic activity) is considered as 100

• Periheral and nuclear modifications are done to the
morphine ring and the activity is compared

• Narcotic antagonists used to counteract the effects of

– (especially to counteract the depression of respiration)

• Drugs used to counteract the effects of narcotics are

• Nalorphine hydrochloride

• Levallorphan tartarate

• Naloxone hydrochloride

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