Anticholinergics are drugs that inhibit the pharmacological response of acetylcholine (Ach) by competitively binding to and blocking muscarinic receptors. Their general structure consists of two carbocyclic or heterocyclic rings (R1 and R2) connected by a chain with an ester or ether group (X) and a basic nitrogen substituent. The R3 group can be hydrogen, hydroxyl, or hydroxymethyl. Maximum potency is seen with 2 carbon units between the ring and nitrogen. Older anticholinergics like atropine and scopolamine are non-selective for muscarinic receptor subtypes, while newer drugs show selectivity. Anticholinergics are used to treat

1. Anticholinergics
Acetylcholine (Ach)
Drugs that directly inhibit
pharmacological response of Ach

2. Muscarine antagonist/antispamodics
• These drugs block the response of Ach in the
muscarine receptor by competitively binding to
it and inhibiting any response.
• They have opposite pharmacological
response of Ach ie if Ach agonist slows heart
rate then Ach antagonist speeds heart rate or
if Ach relaxes bladder then it antagonist
constricts it

3. • Their medical use is in
– in Sooth muscle spasm
– in cold n flu (to reduce nasal secretion)
– previously in ulcer (but now replaced by H2
antagonist and proton inhibitors)
– Overactive bladder (to much urination)
– Motion sickness
– Treat organophosphate poisoning (still doesn’t
work in aging and doesn’t treat respiratory failure)
– Parkinson (brain disease where nerves start
degrading and person slowly goes crazy)

4. SAR of anticholinergics
• Atropine was the first drug of this type and
was used to generate SAR. It was noted that
unlike Ach, the terminal ester carbon in
Atropine had a bulky substituent. This was
considered important and modifications were
done there

5. R2 n
C X (CH2) N substituent
General framework of Anticholinergics
1) The R1 or R2 groups must be carbocyclic or
heterocyclic, but if both are cyclic it gives
maximal antagonist potency. The rings may
be same or different. One of is generally
aromatic and other is saturated ring or olefinic
group (ie it has a C-C double bond)
•Rings may be same or different
•The benzene could be any type
Cyclohexane (non-aromatic carbocyclic
or pyridine (aromatic heterocyclic)
or Pyrrolidine (non-aromatic heterocyclic
R1
R3

6. R1
C X (CH2) N substituent
R3
R2
Detect R1-R3 and X

7. 2)The R3 group can be hydrogen, hydroxyl (-OH)
, hydroxymethyl (-CH2OH), amide ( ) or a
component of the R1 and R2 group. Best
potency is seen with hydroxyl or
hydroxymethyl (this hints that the oxygen
group must be participating in H bond)
Hydrogen Hydroxyl Hydroxymethyl
Amide
Component of R2 and R3

8. 3) The X is mostly ester in most potent
derivatives but it can be a ether oxygen or
absent completely
Mostly ester Or else ether Or absent completely

9. 4) The N substituent cab be both quaternary
ammonium salt or tertiary amine with
different alkyl groups. Most potent
derivatives have quaternary ammonium salt.
The alkyl group is not restricted to only methyl
(as in SAR of Ach agonist). It can be ethyl,
propyl or isopropyl.
Quaternary form
is most potent Alkyl = methyl
Alkyl = ethyl Alkyl = isopropyl

10. 5) The distance between the ring substituted
carbon and nitrogen is not fixed ie it can vary
The no. of alkyl units between that carbon and
nitrogen can vary from 2-4, with most potency
in case of two CH2 units.(this is also unlike
SAR of Ach agonist where the CH2 units
should not be more than 2).
2 CH2 units is
best distance
2 CH2 units (don’t
count O or N, just C)
3 CH2 (don’t count double or
triple bonded carbon. Only
count single carbons)

11. summary
R1
• The R1 or R2 groups must be carbocyclic or
heterocyclic
• The R3 group can be hydrogen, hydroxyl (-OH),
hydroxymethyl (-CH2OH), amide or a component of
the R2 and R3 group
• The X is mostly ester in most potent derivatives but it
can be a ether oxygen or absent completely
• The N substituent cab be both quaternary ammonium
salt or tertiary amine with different alkyl groups
• The distance between the ring substituted carbon and
nitrogen is not fixed but maximum potency requires
about 2 carbon units
• (Note: The SAR does not say anything about selectivity
for muscarinic subtypes)
C X (CH2) N substituent
R3
R2

12. What happens during muscular spam?
• A muscle spasm, or muscle cramp, is an
involuntary contraction of a muscle. Muscle
spasms occur suddenly, usually resolve quickly,
and are often painful. Both skeletal muscle and
smooth muscle are effected by it.
• Spasms may occur when a muscle is overused
and tired, particularly if it is overstretched or if it
has been held in the same position for a
prolonged period of time. The muscle becomes
hyperexcitable, resulting in a forceful contraction

13. Contrast between SAR of Ach agonist
and antagonist
A) Nitrogen group
• In agonist the N can only be quanternary but
• In antagonist N can be both quanternary or
tertiary
Methacholone

14. B) Ethylene group
• In agonist the no of ethylene is fixed at only 2
but
• In antagonist no of ethylene can range from 2-
4
carbamate
Bethanecol

15. C) Selectivity
• In agonist the methyl substitution in ethylene
group controls selectivity of muscarinic or
nicotinic but
• In antagonist no such feature is present. Still
It only antagonizes muscarinic only
Methacholone
Muscarinic selective

16. D) Ester group or X group
• In agonist ester is not needed and can be
removed but an Oxygen must exist in it’s
place
• In antagonist ester is not needed and can be
removed but an Oxygen need not exist in it’s
place

17. O
H2N O
CH2 CH2 N(CH3)3
H3C O CH2 CH2 N(CH3)3
O
H3C CH2 CH2 N(CH3)3
Mostly ester
Oxygen in place
on ether
Oxygen absent
Ester
Ether
Ketone

18. E) Rule of five and terminal carbon
In agonist rule of five is followed and terminal
carbon is bonded to Hydrogens
In antagonist, rule of five is not followed and
the terminal carbon is bonded to two bulky
ring groups
Methacholone

19. Spot the associated functional groups

20. Specific Muscarinic antagonists
• Aminoalcohol esters
– Atropine
– Scopolamine
• Aminoamide
– Tropicamide
• Aminoether
– Benztropine
– Orphenadrine
• Micellneous
– Solifenacin
– Darifenacin
While all of these are selective to
muscarinic receptor
they are not selective to a specfic
subtype eg M1, or M2 etc. Only
the last two Solifenacin and
Darifenacin show selectivity to
M3.

21. NCH3
O
O C
CH
CH2OH
NCH3
O
O C
CH
CH2OH
O
Atropine
Scopolamine
Dicyclomine Tropicamide

22. Atropine
NCH3
O
O C
• It is anticholinergic that blocks muscarinic receptors
• It is an alkaloid extracted from Solanaceae plant and was the first
anticholinergic.
• It is an ester of tropine and tropic acid and used as a sulphate Salt
in racemic from
• At therapeutic does it can penetrate the brain and stimulate the
CNS
• Uses
– Treat Bardycardia
– Reduce secretion before surgery
– Treat Iritis (painful inflammation of eye)
– Organophosphate poisoning (only to decrease muscarinic action, not an
antidote like PAM)
• MOA – It competitively binds to muscarinic receptor and
antagonizes it thus blocking all cholinergic effects
CH
CH2OH

23. Atropine synthesis
HC
NCH3
Esterification
with HCl
(-H20)
NCH3
O
O C
CH
CH2OH
OH
CH2OH
O
HO C
Tropine Tropic Acid
Atropine

24. O
Scopolamine
O
NCH3
O C
• It is anticholinergic that blocks muscarinic
receptors
• It is an alkaloid extracted from Solanaceae plant
• It is used as salt hydrobromide salt in enantiopure
(-) form
• At therapeutic does it depresses CNS
• Uses
– Treat Iritis (painful inflammation of eye)
– Treat Parkinson
– Treat Motion sickness
CH
CH2OH
• MOA - It competitively binds to muscarinic
receptor and antagonizes it thus blocking all
cholinergic effects

25. Dicyclomine
• It is an anticholinergic that blocks muscarinic
receptors
• It is a weaker antagonist than atropine and
doesn’t stimulate the brain
• Uses
– treat intestinal hypermotility (causes constipation and
diarrhea and decreased opportunity for the
absorption of nutrients)
– irritable bowel syndrome (a disorder in large intestine
that causes cramping, abdominal pain, bloating, gas)
• MOA - It competitively binds to muscarinic
receptor and antagonizes it thus blocking all
cholinergic effects

26. Synthesis
CH2CN
Phenyl acetonitrile
Br
H2C CH2 CH2 CH2 CH2 Br
1,5-Dibromopentane
-2HBr
CN
Cyclohexane derivative

27. Saponification
COOH
i) HCl
HO CH2 CH2 N
C2H5
C2H5
ii) Reduction
C O CH2 CH2 N
C2H5
C2H5
O
.HCl
Dicyclomine Hcl

28. Tropicamide
• It is an anticholinergic that blocks muscarinic
receptors
• Its duration of action is shorter than Atropine
• Uses
– Mydriatic (drug that dilates pupil)
– Cycloplegia (to fix eye movement)
• MOA - It competitively binds to muscarinic
receptor and antagonizes it thus blocking all
cholinergic effects

29. COOH
Synthesis CH
O
CH2OH H3C
C Cl
Tropic acid Acetyl Chloride
Esterifcation
COOH
CH
O
CH2O C CH3
SOCl2
C
CH
O
CH2O C CH3
O
Cl
Tropic acid acetate
An acid chloride

30. C2H5
HN H2C N
O
C
CH
C2H5
N CH2 N
CH2O C
O
CH3
Tropicamide acetate
Saponification
O
C
CH
C2H5
N CH2 N
CH2OH
Tropicamide

31. Newer Muscarinic Antagonist
• Newer drugs focus on subtype selectivity and
don’t have defined SAR
Older SAR based non-selective drug
Selective to M1 Selective to M2
Observe the use of tri-cyclic ring and how minor modification changed
Selectivity from M1 to M2. This is true not just here in in every case

32. Acetylcholine and muscle contraction

34. Ach binds to
it’s receptor in
muscle
Myosin cross-bridges
with
Actin leading
to contraction
Action
potential
(AP)is
generated
AP causes
Release of
Ca2+ from SR
Muscle return
back to
relaxed state
AP ends and
Ca2+ is put
back into SR
Events during Muscle contraction

35. Events during an action potential
Depolarizing blockers
keep maintaining
depolarized state
An action potential is a temporary “all or nothing” changes in cell
membrane potential. During this period cell is taken from polarized to
depolarized state

36. Nicotinic antagonist
• Nicotinic Antagonist competitively bind to
nicotinic receptors and block nicotinic response
which results in blockade of skeletal muscle
contraction ie paralysis
• There are two types
– Neuromuscular Blockers (not the same as skeletal
muscle relaxant that work by CNS depression)
– Ganglionic Blockers
(We will only discuss the first)

37. Neuromuscular Blockers
• The first Neuromuscular Blockers was
extracted from the plant cucare which
contained Tubocuraine.
• It was noted that given in normal condition,
they cause muscle paralysis.
• Tribesmen of Amazon used it in their arrows
for hunting.
• The poison will cause respiratory failure in the
prey

38. Therapeutic application
• As an Adjunct to general Anesthetic ,(general
Anesthetic are drugs that makes you
unconscious for surgery) they lower the dose
of Anesthetic thus lowering side effects and
promoting postanesthetic recovery time and
• Tracheal intubation (putting tube inside food
pipe) or endoscopy (putting tube inside
rectum)
• Correct bone dislocation
• 2 types
– Non-depolarizing (desired property)
– Depolarizing (undesired property)

39. SAR
• Two quaternary ammonium salts separated by
10-12 carbon units is the only known general
requirement. This follows from the
observation that nicotinic receptor has two
cationic site
N
H3C
H3C CH2 N
H3C
CH3
CH3
CH3
10
Decamethonium bromide

41. Succinylcholine Chloride
• It is a depolarizing neuromuscular blocker. This
depolarization effect makes the muscle fiber resistant to
further stimulation by Ach. This nature makes it
therapeutically undesirable in comparison to the Non-depolarizing
blockers
• It is a dimer (two same molecules joining each other) of
acetylcholine molecules
• Like Ach, it’s is rapidly metabolized in blood and thus
has short duration of action of about 6 to 8 mins
• Uses
– Endotracheal insertions
– Endoscopy
• MOA – It antagonizes nicotinic receptors at
neuromuscular junction which causes skeletal muscle
paralysis

42. Think of modification to improve
duration of action of Succinylcholine
Chloride
Hint- Rapid metabolism is due to hydrolysis of ester
O
O
O
O
CH2
CH2
CH2 N{CH3}3Cl
CH2 N{CH3}3Cl

43. synthesis
CH2
CH2
O
C
Cl
C Cl
O
Succinyl Chloride
Condensation
-2HCl
2HOCH2CH2N(CH3)2
CH2
CH2
O
C
OCH2CH2N(CH3)2
C OCH2CH2N(CH3)2
O
CH3Cl
Methyl
chloride
CH2
CH2
O
C
OCH2CH2N(CH3)3
C OCH2CH2N(CH3)3
O
.2Cl
Succinyl Choline Chloride
Dimethyl animo
ethanol

44. D-Tubocuraine
• It is a Non-depolarizing neuromuscular blocker. It doesn’t
make the muscle fiber resistant to further stimulation by
Ach.
• This nature makes it therapeutically desirable in
comparison to the depolarizing blockers
• It is metabolically stable, only 1 % is degraded by liver, thus
acts for a longer period of about 80-120 mins
• It’s preparation includes bisulfites (an anti-oxidant) which
causes histamine release thus can cause allergic reactions
• Uses
• MOA – It antagonizes nicotinic receptors at neuromuscular
junction which causes skeletal muscle paralysis

45. Point to be noted
• Being metabolically allows drug to be active
for longer periods but it also means that the
only way to get rid of their effect is excretion
through the kidney.
• Thus in patients with kidney failure, such
characteristic can cause trouble. An ideal drug
must be readily expelled from body. In such
case does might need to be lowered.

46. Thank You

47. Drugs from Plants and HTS
•Historically, Plants have always been the source of the first drugs in a class. Both
Atropine and Tubocuraine were the first of their kind and notice they were all
alkaloids, along with Physostigmine .
•The only downside to this process is that there are thousands of plants and each
plant typically contain a multitude of compounds, that testing for each and every
one against a receptor/enzyme is a very exhaustive process.
•Thankfully, the industry can test thousands of compounds in few days using High
Throughput Screening(HTS) which are automatic and robotic system. To use it first
we have to design as assay. This is now available in academia too.
Drug Plant Class Chemical
Type
Atropine Solanaceae Antimuscari
nic
Alkaloid
Tubocuraine Curare Antinicotinic Alkaloid
Physostigmi
ne
calabar
beans
Reversible
AChE
inhibtor
Alkaloid

48. • In these systems drugs/compounds are injected into
plates that contain many hole which actually is a
individual assay that contains receptor/enzyme on
which we desire to find if the drug has any activity or
not
• In each hole different drug concentration is injected
• Successful drugs generally gives some kind of visible
color change (colorimetric assay) or change in
fluroscence reading (florimetric assay) in every hole in
the plate. All the data for every hole can be seen easily
in a computer screen
• The intensity of color change and fluroscence reading
allows to both qualify and quantify drug action at that
concentration
• If a compound is having good activity, medicinal
chemists alter it to improve potency/selectivity

49. HTS machine looks like this
For more info:
Watch this video https://www.youtube.com/watch?v=EQC5MViYCtI
Read : http://ajpcell.physiology.org/content/286/3/C465