Narcotic Analgesics-Medicinal Chemistry

Introduction, classification, Structure activity relationship, mechanism of action, synthesis and uses of narcotic analgesics

1. Dr. Gopal Krishna Padhy

2. Analgesics are defined as drugs that selectively relieve pain

by acting in the central nervous system or on peripheral pain
mechanism without disturbing consciousness

These are mainly divided into two types.
o Narcotic analgesics
o Non-narcotic analgesics

3. Narcotic analgesics

oNarcotic analgesics are also known as opoid analges
o They relieve severe pain by acting mainly on the fl
nervous system.

> The oldest and the best narcotic analgesics are opium
alkaloids

The narcotic analgesics are potentially addictive.

If intake of the drug is stopped, very undesirable withdrawal
effects like sever pain, sweating, salvation, hyperventilation,
restlessness and confusion are observed

5. NCH;

Levorphanol

N-CH3

Dextromethorphan

6. HC,

7
C=CH—chz

H3C
Pentazocine

Metazocine

7. Y

| 4-Phenylpiperidine analogues |

COOC:Hs
HsC-N NC-C-CH3-CHy—N

Meperidine / Pethidine Diphenoxylate

COOC¿Hs

Anileridine

8. 4-anilinopiperidine analogues |

o
Os À O0)

Fentanyl

H¿COH2C
lo)

A

Sufentanyl

9. [Diphenyl Propylamine derivatives |

9 Hs
CyHs-C-O-C—CH—CHp-N
TEE y

CH, CH; CH

9 CHs Cha
CHs—-C—C-CHo—CH—N
CHs

Methadone Propoxyphene

10. Y

Y Narcotic analgesics produce their actions at a cellular level
by by activating on opioid receptors.

Veg. Morphine and its derivatives act as agonists of the mu and
kappa opioid receptors.

Y These receptors are distributed throughout the (CNS) and

also been found on peripheral afferent nerve terminals .

Y Opioid receptors are coupled with inhibitory G- proteins

and their activation has number of actions like closing of
voltage sensitive calcium channels, stimulation of
potassium efflux leading to which causes
reduction in neuronal cell excitability.

11. Morphine

K
channels
open

Cell becomes
Ca** hyperpolarized
entry
blocked ——> | [Ca**Ji

Decreased
release of
neurotransmitters

12. «The structure of morphine is composed of five fused
rings and have 5 chiral centers.
* the levo (-) rotary form is the active form while dextro (+)

morphine 1s Inactive.

* The A ring and the basic nitrogen are the two necessary

component in every potent opoid receptor agonist.
° The aromatic A ring and the tertiary nitrogen may be

connected by an ethylene/propelene linkage.

Phenolic OH HO.

Ether bridge Tertiary Nitrogen

Alcoholic OH

13. * The substituent on nitrogen of morphine and morphine

like structure is critical to degree and type of activity.

* N-methyl substituents generally results in compound with
good agonist proporties.

* Increasing the size of the N-substituent results in

antagonist e.g. naloxone

HO. O
a © N-CH2-CH:CH,

O

Naloxone

14. | ión]
* Masking the phenolic hydroxyl group by etherification to
methyl ether decrease the analgesic activity about ten fold.

e.g. Codeine H5CO.

Codeine
a N-CH3 =

HOTS

+ Esterification of hydroxyl group leads to more active

compound than morphine. e.g. Heroin

* introduction of hydroxyl group at pa position lead to

increase in activity e.g. oxymorphone

HO O
Oxymorphone
a © Nc 1

14

©

15. Y

* Change in the C-ring chemistry of morphine can lead to

compounds with increased activity. e.g. Hydromorphone is 8-10

times more potent than morphine.

HO.

N-CH3

Hydromorphone

16. * Removal of 4,5-epoxide bridge in the morphine structure
results in mophinans.

* only levo isomer of morphinan possess opoid analgesic
activity while dextro isomer have antitussive actvity.

* levorphanol is 8 times more potent than morphine.

HO.

Levorphanol
4
N-CHa

5
c

*Compound that lack both epoxide bridge and the C ring of

morphine retain opoid analgesic activity. e.g,

Benzomorphans.

17. CH NaNH> CH
+ CI-CHz-CH-NICH3)z as DE ii CH-N(CHg)a *

Diphenylacetonitrile Nucleophilic
1-chloro-N, u ‚addition reaction

H30, H* CH

ose Hydrolysis Ú
CH¿-CH-N(CHa)a en C—CH;-CH-N(CH3)>

NH —C=N

MOA-In addition to activity, methadone also act as
of the N-methyl-D-aspartate ( ) receptor and it strongly

and

Uses-Methadone is indicated for the management of enough
to require an opioid analgesic and for which alternative treatment options
are inadequate. It is also used in treating , since it replaces

other agonists on the receptor. 0

18. Y

H

0 / o
H¿C-CH¿-C=CI + wy Na H:C-CH-C- < m + CiCH-0h;(

Propionyl Chloride

N-phenylpiperidin-4-amine

lo)

Ie-enz-en ook)

: Similar to morphine

It is uses both independently and in combination with
droperidol for preanesthetic medication, in different forms of
narcosis, and in post-operational anesthesia.

19. Uses: Morphine is prescribed in
all cases when NSAID action is
not sufficient and requires the use
of strong opioid analgesics. It is
widely used in
and for
It is used in
and in few
forms of
It is used in surgery as a

before

the general anesthesia procedure

begins.

Ho

MOA: Similar to morphine

Uses: This drug is very effective
in oral use and is used for average
to moderate pain. It is often used
as an . Codeine is
used to treat mild to

20. N-CHs

MOA: Levorphanol has a

similar mechanism of action

compared to methadone.

Uses: This drug is
recommended for relieving
in

and surgery.

MOA: Levorphanol has a similar
mechanism of action compared
to methadone.

Uses: For treatment and relief
of

21. COOC2H;
HsC-N

MOA: Similar to morphine
Uses: Meperidine is used to
help
Meperidine is
widely used as
It is preferred in

due to its

quick onset and short-lasting

action.

COOCHs

MOA: Similar to morphine

Uses: Anileridine is a synthetic
opioid and strong analgesic
medication. It is a narcotic pain

reliever used to

22. MOA: Diphenoxylate is an

receptor that
stimulate to
decrease the peristalsis and
constrict the sphincters.
Diphenoxylate has a direct
effect on circular smooth
muscle of the bowel, that
conceivably results in

segmentation and prolongat ion

of gastrointestinal transit time.

Uses: it is mainly used for
treating . It helps to
decrease the number and
frequency of bowel

movements.

MOA: Similar to diphenoxylate
Uses: This medication is used to
treat (including

). Loperamide
is also used to reduce the
amount of discharge in patients

who have undergone an

23. CH;
-C—CH—CH2-N
CH), CH3 CHs
7

Nr

MOA: Similar to morphine
the relief of mild to

Uses: For
moderate

pain.

24. An opioid antagonist, or opioid receptor antagonist, is a

receptor antagonist that acts on one or more of the opioid

receptors.

Examples: Naloxone and naltrexone

no.
° D O
o
N—CHy CHE CH:
A
nn

o Naloxone Naltrexone
MOA: They are competitive antagonists that bind to the opioid
receptors with higher affinity than agonists but do not activate the
receptors. This effectively blocks the receptor, preventing the body
from responding to opioids and endorphins.

Uses: Naltrexone is exploited in treatment of opioid addiction.

25. Wilson and Gisvold, Text book of organic, Medicinal

and Pharmaceutical Chemistry.

«e Foyes Principles of medicinal chemistry by Williams
O. Foye.

*% A Text book of medicinal chemistry (Synthetic and
Biochemical Approach) vol. I& II by SN Pandeya.

“Synthesis of Essential Drugs by R.S. Vardanyan and
V.J. Hruby