Lecture Notes for Med Chem/ CNS drugs/ B pharmacy of Purbanchal University, Nepal

1. Opiod Analgesics

2. • Analgesics- substance that relieves
pain
• Narcotic analgesics are drugs that
can relief pain without causing
narcosis (loss of consciousness)

3. Uses
• Choice of drugs for managing chronic pain as
with cancer or RA
• Used as inducing agent (fentanyl) or analgesic
supplement with General anesthetics
• They have clinical use as anti-diarrheal and
antitussive eg Loperamide and Dextromorphan
• Some opioids such as methadone and
buprenorphine are used to counter addiction of
more potent opioids such as heroin

4. • Opium - is a Greek word meaning “juice,” or the
extract of seeds from the poppy Papaver
somniferum
• Morphine was the first Narcotic analgesic isolated
from opium which contains over twenty distinct
alkaloids
• Opiates – synthetic/natural compounds both
structurally and pharmacologically similar to
Morphine
• Opiods – synthetic/natural compounds not
structurally but only pharmacologically similar to
Morphine

5. Pain and its types
• Pain is an uncomfortable/unpleasant physical
or psychological sensation in the body.
• Pain is a good thing. It warn us of something
damaging our body so we take proper medical
care
• However, constant pain can reduce quality of
life

6. Pain has a psychological side .
Once you accept pain, it may not be painful anymore

7. • Acute pain : sharp, short term pain
– Surgery, Broken bones, Burns, Sprain, Labor
It is cured if the caused of the pain is removed
or treated
• Chronic pain: dull, long term pain
– Cancer, arthritis, chronic back pain and knee pain,
Migraine
Pain exists for months even when the injury is
healed. Cause not well understood

8. How do we feel pain?
• Pain receptors or Nociceptors are found on the free nerve
endings of primary sensory fibers that detect unpleasant
stimuli and pass the information to CNS to be interpreted as
pain
• They are distributed all over the body (skin, muscles, joints,
internal organs but not brain)
• When tissue gets damaged by certain (mechanical, thermal or
chemical) stimuli, it releases inflammatory mediators (eg
bradykinin, serotonin, prostaglandins, cytokines, and H+)
which can activate primary nociceptors
• When these neurons reach the spinal cord, they pass the pain
signal to 2ndary sensory fibers located around the spinal cord
where key NT is substance P.
• The 2ndary sensory fibers transmits information to brain
where it is interpreted as pain.

9. Ways to relieve Pain
• GA – affect chemical component of neuro
transmission ( GABA n NMDA receptor)
• LA – block electrical component of neuro
transmission (VG Na+ channel) (especially for
pain)
• NSAIDS – Block local pain messenger such as
prostaglandin
• Opiods- block both chemical and electrical
component of nerve transmission
Except NSAIDS all three are CNS depressents

10. Analgesic receptors
• Body has mechanism to naturally relief pain
• There are three types in brain and spinal cord
• µ (mu) --> most widely occurring and target of
most drugs
• Κ (kappa) --> lack respiratory depressing effect
and can counter analgesic effect of µ agonist
• δ (delta) --> reduced GIT motility, respiratory
depression, convulsant effect limited clinical use
• Only µ and Κ have clinical use

11. Mechanism of action
• Opiod analgesic agonize opiod receptors µ,κ and δ
which are G-protein couples receptors. This leads to a
series of event which ultimately block neuronal pain
transmission by:
1. Inhibition of activation of voltage gated Ca+2 channels
which depresses NT release
2. Increases K+ conductance outside the cell to cause
hyper polarization of cell thus reducing it’s excitability
3. Inhibtion of adenyl cyclase
(adenyl cyclase--> cAMP --> PKA --> phosphorylation of
ion channels --> increase chances of channel opening)

12. Three effects of opiod receptors

13. Opioids - Classification
1. Natural Opium Alkaloids: Morphine and Codeine
2. Semi-synthetic: Buprenorphine, Oxycodone, Diacetylmorphine(Heroin)
3. Synthetic Opioids:
• 4-Phenylpiperidines: Loperamide and Fentanyl and Meperidine
• Diphenylpropylamine derivatives: Loperamide and Methdone
• Benzomorphans: Pentazocine, Phenazocine
• Morphinan : Levorphanol and Butorphanol
4. Endogenous opioid : natural pain relieving peptides of the body, such
as endorphins, enkephalins and dynorphins
5. Miscellaneous : Tramadol, Meptazinol

14. SAR
Modification to Morphine

15. 1. Morphine has 5 Chiral centers. Only the
Levo(-) rotatory isomer is active

16. 2. The OH group in the phenolic ring and basic
Nitrogen is needed for activity and seen in all
potent µ agonist.
Activity can be preserved or enhanced by
removing other rings
Changing -OH to just –H or -OCH3 lowers activity
as seen with codeine
R= C3
substituent
Activity effect
-H 10X Decrease
-OH morphine
-OCH3
(codeine)
Decrease

17. Morphinans
Benzomorphine
4-Phenylpiperidines
Fig: Loss of other rings doesn’t effect analgesic activity.

18. How many chiral centres?

19. 3. The Nitrogen is mostly tertiary with a methyl
substitution in morphine. The size of
substituent on Nitrogen dictates potency and
agonist or antagonist activity.
a) Increasing size from methyl (ie 1 C) to 3 or 5
carbon (especially with double bonds or
small cyclic/aromatic rings) results in
antagonist activity
b) Still larger substitution restores agonist
activity in more potent form

20. •If R = 3-5 carbons then µ antagonist effect
(more valid if presence of double bond or Small carbo-cyclic ring)
•If R = > 5 carbon (in chain or ring ) then increased µ agonist effect
R= Nitrogen
subtituent
effect
CH2CH=CH2
(3 C with
double bond)
Becomes µ antagonist
CH2CH2Ph
(Total 8 C)
µ agonist (10X more potent than
morphine)

21. 4. Reduction of 7,8 double bond increases
activity
5. Inclusion of Hydroxyl group at 14 increases
activity
Activity
increases
Activity
increases
OH at C14
7,8 Reduction of double bond
to single bond

22. 6. Removal of Hydroxyl at 6 increases activity
7. Oxidation of Hydroxyl to keto group at 6 increases activity, if
there is also reduction of 7,8 double bond eg hydrocodone
8. Acetylation of Hydroxyl at 6 increases activity
R= C6 substituent Effect in activity
H increase
=O (keto)
=O (keto) with 7,8 redcution (change
double bond to single)
Decreases
Increases (10X more potent than
morphine
H3CC=O (acetyl) Increase

23. 9. Removal of the ether linkage produces
compounds called morphinans that has
increases activity
Activity increases
No ether linkage
Levorphanol (10X potent than morphine)

25. Morphine
• It is a naturally occurring analgesic alkaloid extracted from
opium of poppy plant
• Modification to it’s structure has resulted more potent
compound
• Used in chronic pain management
• It’s 3-O-glucoronidation metabolite is inactive
• But it’s 6-O-glucoronidation form is active and thus does
reduction is needed in case of renal damage (coz it’s rate of
clearance is reduced)
• It is potent enough that it’s 60mg oral dose has analgesic effect
equal to parental administration
• MOA: agonizes µ receptor which depresses pain signals by
• inhibiting VGCC and prevent release of Neurotransmitters
• Opening VGPC and causing hyperporalization of nerves cells
• Inhibiting adenyl acylase

26. Codeine
• It is weak µ agonist formed by modification of 3OH
in morphine into H3CO. This results in loss of activity.
Thus codeine is used in moderate to mild pain only.
• It s metabolic product is morphine and thus abused
by addicts.
• The does requires to produce analgesia after
parental dose causes release of histamine that in
turn causes allergic responses. Thus not used
parenterally
• Use limited as antitussive drug

27. Heroin
• It is 3,6-diacetyl derivative of morphine
• By itself is a weak U agonist but the diacetyl form
increases its lipophilicity and enhances its
penetration into brain
• Also it metabolic product, 6 acetyl morphine, is more
active than morphine
• These two factors make it more potent than
morphine but it’s use it limited by extreme addiction
to it (more potent = more addictive)

28. Meperidine
• It is a 4-Phenylpiperidines based derivative of
morphine
• A weak µ agonist, 1/10th as potent as morphine
• Doesn’t inhibit cough
• rapid onset of action but high 1st pass metabolism
• Thus used in obstetrics, where given in small does
to mother it won’t cause respiratory depression
to the newborn

29. Fentanyl
• It is a 4-(Phenylpropionamido)piperidines
based derivative of morphine
• It is about 80 times more potent than
morphine
• It Does not cause histamine release on IV
injection (ie no skin inflammation)
• It Inhibits p-glycoprotein mediated efflux of
digoxin (ie increases conc of digoxin in blood)

30. Buprenorphine
• It has a mixed Agonist/antagonist effect
• It produces 50% analgesic effect about 20-50
times than morphine but can NEVER produce
100% effect
• Potent Partial agonist of µ and κ receptor but
antagonizes δ receptors
• Advantage of less severe respiratory depression
and less incidence of tolerance or addiction
• Used to block effects of high dose of heroin
• It itself can’t be antagonized by Naloxone

31. Pentazocine
• A mixed agonist/antagonist effect
(µ antagonist and κ agonist)
• weak analgesic effect - 1/6 as potent as
morphine
• Since it is a κ agonist it produces dysphoric effects
and also increases blood pressure and heart rate
• Abused drug – when injected with
tripelennamine (an antihistaminic) it increases
euphoric effect and decreases dysphoric effect

32. Tramadol
• not a true opiod analgesic
• (+) isomer has activity 1/3800 that of morphine!
• (-) isomer blocks norepinephrine and serotonin
(excitatory NT) reuptake and thus show some
analgesic activity. But the effect is weak
• It’s metabolite is active and 1/35 as effective as
morphine.
• Non-addictive, no respiratory depression or
constipation
• Used with other analgesic for synergistic effect

33. Naloxone
• It is a strong opiod antagonist
• High affinity for µ but low affinity for κ and δ
• It is used as a emergency drug to counteract life-
threatening depression of the CNS and
respiratory system due to morphine or heroine
overdose
• It itself is not anxiolytic but can potentiate the
subtherapeutic dose of the anxiolytic drug
busiprone (ie less does of busiprone can be given)

34. Preparation of Morphine from Poppy plant
1. 10-15 kg of raw opium plant is boiled with 115 kg of water.
The opium alkaloids are eventually extracted into the boiling
water
2. calcium hydroxide, Ca(OH)2, is added to the solution. This
converts the water insoluble morphine into the water
soluble calcium morphenate. Codeine is slightly water
soluble and gets carried over with the calcium morphenate
in the liquid.
The other opium alkaloids are neither water soluble nor
react with the lime to form soluble calcium salts.
They are filtered off and now there is only morphine salt and
codeine in the solution

35. 4. The clear liquid is filtered and reheated and
Ammonium chloride (NH4Cl) is added to adjust the
alkalinity to a pH of 8 to 9, and the solution is then
allowed to cool. Within one or two hours the salt
form of morphine turns into insoluble neutral form
and precipitate out of the solution
5.The solution is filtered and the residue containing
the morphine is dried in the sun. When dry, the
crude morphine base is a coffee-colored powder.
Approximately 13 kg of opium, from one hectare of
opium poppies, are needed to produce 1.3 kg of
morphine

36. 1) Morphine + Ca(OH)2 = calcium morpheate
2) Calcium morpheate + NH4Cl = CaCl2 + NH3 + neutral morphine

37. Physical dependence/Addiction to
narcotics
• All forms of drug addiction are driven by
stimulation of brain’s self-reward system
• Self reward system refers to activity of
neurotransmitter Dopamine(DA) which has
euphoric effect (intense feelings of happiness,
excitement, and joy)
• Any Drug that concentrate DA in the synapse by
– stimulate DA release,
– Inhibit DA reuptake or
– Inhibit DA degradation have addition potential

38. • µ agonist stimulate release of DA, ie causes
euphoria, whereas κ agonist prevent DA
release ie causes dsyphoria (this effect limited
its clinical use)
• Cocaine prevents reuptake of Dopamine at the
synapse and thus prolong the duration and
intensity of reward response

39. • But the self reward system is self-limiting ie after
prolonged or repeated activation feedback mechanism
blocks the euphoric effect. Thus the effect lasts for a
short while but with opiods, the euphoric effect is very
intense. This short but intense feeling of happiness is
termed as “euphoric rush” and is very addictive.
• Drugs that slowly distribute to the brain have less
addiction potential because the feedback system can
respond quickly
• Only fast distributing drugs, that are potent too, are
successful to cause a “euphoric rush”
• Distribution into the brain is governed by the
lipophilicity and thus abused drugs are very lipophillic
to allow quick distribution and quick action.
• Also route of administration is lungs or IV to cause
quick distribution (thus oral dosage has less addiction
potential)

40. Tolerence
• Tolerance means the need for higher doses to
produce same level of effect
• When an agonist binds to µ receptor,
– G second messenger proteins are activated
– and adenyl cyclase are inhibited
• On continuous binding, tolerance develops due to
– Decreases synthesis of G protein subunits
– upregulation of adenyl cyclase to compensate the
decreases cellular levels of cAMP.

41. Withdrawal
• Stopping intake of opiods produces unwanted
physiological effects called withdrawal symptoms
• Within 24 hrs following effects are seen
– muscle aches, restlessness, anxiety, lacrimation (eyes
tearing up) runny nose, excessive sweating, inability
to sleep
• After 24 hrs more intense effects are seen
– Diarrhea, high BP, nausea, vomiting rapid, heart beat

42. • Cells resist opiod mediated decrease in adenyl
cyclase by upregulating (increases production)
adenyl cyclase.
• If opiods are withdrawn, this upregulated
adenyl cyclase in turn generates more cAMP.
• This increased cellular levels of cAMP causes
many abnormal effects

43. Revision
• Body has pain receptors that recognize pain
stimuli
• But Opiod analgesics don’t work by blocking
these pain receptors

44. • Body also has opiod receptors (anti- pain
receptors)
• Opiod drugs bind to them and strengthen
their anti pain functions (ie they agonize opiod
receptors)

45. • Blocking pain receptors can also produce
analgesic effect but…..
• …….No analgesic drugs exist that block pain
receptors

46. • The reason for addictive nature of opiods is
not because they help manage pain
• But because they cause euphoria through
stimulation of dopamine

47. • There are 3 opiod receptors: µ (mu), κ (kappa),
δ (delta)
• Most clinical analgesic bind to µ
• κ has dysphoric (extreme depression) effect
• δ has high respiratory and convulsive effects

48. • µ agonist promotes dopamine release that
causes addiction
• κ agonist blocks dopamine release leading to
extreme depression that can cause suicidal
tendency
• δ agonist do not exist
seems like we are stuck with addictive analgesics!!!

49. Mixed agonist/antagonist
Q) How can some opiod drugs be both an
agonist and antagonist at same time?
Ans. There is not 1 but 3 opiod receptors.
It is possible to Agonize at one opiod receptor
and Antagonize another opiod receptor
Eg Buprenorphine is agonist of µ and κ receptor
but antagonizes δ receptors

50. Q) Are people addicted to opiod
analgesics for their pain managing
effects?
Ans) No. Opiod drugs potentiate the
effects of dopamine at the synapse.
Dopamine is a neurotransmitter that can
induce euphoria which is an intense feeling
of happiness, excitement, and joy. The
addiction is for this euphoric effect.

51. Q) Why do addicts prefer IV or
inhalation than oral route?
Ans) With oral route, there is 1st pass
metabolism and slow absorption. Thus the
drug does not accumulate in brain quickly or
at enough concentration to produce the level
of euphoric rush that other routes can do
because they bypass 1st pass metabolism and
directly put drug in blood.

52. Q) What are the two important characteristics of
drugs that cause addiction?
i) Their receptors must be involved in
potentiating dopamine effects at the synapse
ii) They must have access to the brain ie must be
lipophillic enough to cross the BBB

53. Q) Heroine is only 1/10th as potent as morphine.
So why do addict prefer heroine than more
potent morphine?
Two reasons
• Heroine is more lipophilic than morphine ie
quicker BBB penetration
• It’s metabolite is more potent than morphine
• These two factors work together to provide a
intense and quick occuring ‘euphoric rush’
that addicts seek

54. HOMEWORK
Rank potency of these compounds

56. Future of analgesics : addiction free age
• Recycling opiod receptors
• +Naloxone TLR4 receptors
• Nav1.7 receptors
• P2X receptors
• Glial cells
• Snail cone venom
• Opiorphin

58. Recycling opiod targets
• κ agonists that don’t penetrate the brain but
act on peripheral NS don’t cause dysphoria
and are a promising approach since they have
no addiction potential
• Ref : Clin J Pain Volume 26, Number 1, January
2010 Supplement

59. +Naloxone and morphine
• + Naloxlone has no activity on opiod receptors
• Research indicates that cause of opiod
addiction involves other receptors beyond
opiods
• It antagonizes toll-like receptor 4 (TLR4)
• Given together with morphine, it has shown
to reduce addiction of morphine without
interfering it’s analgesic activity
• Ref: J Neurosci. 2012 August 15; 32(33): 11187–11200

60. P2X7 receptors
• P2X receptors are ATP-gated ion channels
whose roles is in pain following nerve damage
and inflammation.
• Inhibiting a subtype, P2X7 seems to cure
– tactile allodynia (pain caused by touch)
– chronic inflammatory pain in animal model

61. Role of Glial cells in pain signalling
• Glial cells are non-neuronal cells that maintain
homeostasis, form myelin, and provide support
and protection for neurons in the brain and
peripheral nervous system
• Neuroscience currently identifies four main
functions of glial cells:
• To surround neurons and hold them in place
• To supply nutrients and oxygen to neurons
• To insulate one neuron from another
• To destroy pathogens and remove dead neurons.

62. • They also have function in glutaminergic and
dopaminergic release pathways
• If morphine can be given with drugs like
AV411, that block glial cells, then no side
effects of morphine can be seen

63. • Systemically active human opiorphin,which protects
enkephalins from degradation, is a potent yet non-
addictive analgesic without drug tolerance effects
• Ref: J Physiol Pharmacol. 2010 Aug;61(4):483-90.

64. What is obstacle in new analgesic
drugs research?
Bad interpretation from animal models
A 2013 research found Oreo biscuits were more
addictive than cocaine in rats!
 drugs did not penetrate correct compartment
in man
Invalid target
Inappropriate patient population for
mechanism

65. Animal based study of anti-inflammatory effect
First Induce inflamation
Then give drug n check if
Inflamation is reduced or not

66. Effective drugs for Neuropathic pain
Neuropathic pain chronic pain due to damaged
nerves it is described as sensation of burning,
stabbing, shooting or like an electric shock.
NSAIDS are useless in this case
Useful drugs are
• Pregabalin – anticonvulsant
• Amitriplline – tricyclic antidepressants
• Duloxetine – antidepressant