II. Drug suppressing the cholinergic activity
(Anticholinergics = Parasympatholytics)

A. Muscarinic antagonists
B. Nicotinic antagonists

1

II. Anticholinergics (Parasympatholytics)

They block muscarinic (cholinergic) receptors of effector cells, such as
smooth muscle, outer gland and heart cells. They do not block the nicotinic
type of cholinergic receptors (receptors in sympathetic and parasympathetic
ganglion cells).

These drugs are also called Anti-Muscarinic drugs. They compete for the
muscarinic receptor with acetylcholine released from vesicles and prevent
only the muscarinic effects of exogenous acetylcholine and
anticholinesterases.

They are also called Spasmolytics, because they remove spasms on smooth
muscles

2

II. PARASYMPATOLITIC DRUGS (ANTICHOLINERGICS)

These compounds have selective effects. The reason for their selective effects
is their ability to reach the site of influence.

The anticholinergic action by drugs apparently depends on their ability to reduce
the number of free receptors that can interact with ACh.

According to suggested hypotheses; that blocking compounds with high affinity
to the receptors act by reducing the number of free receptors or the efficacy of
the endogenous neurotransmitter.

These compounds are defined as cholinergic blocking drugs,
parasympatholytics or cholinolytics. This group of compounds will be studied in
two subclasses.

Muscarinic Antagonists
Nicotinic Antagonists

3
Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, page:572

https://www.slideshare.net/kaami16/cholinergi
c-antagonists-medicinal-chemistry 5

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https://www.slideshare.net/kaami16/cholinergic-antagonists-medicinal-chemistry

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https://www.slideshare.net/kaami16/cholinergic-antagonists-medicinal-chemistry

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https://www.slideshare.net/kaami16/cholinergic-antagonists-medicinal-chemistry

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https://www.slideshare.net/kaami16/cholinergic-antagonists-medicinal-chemistry

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https://www.slideshare.net/kaami16/cholinergic-antagonists-medicinal-chemistry

A. Muscarinic Antagonists Structure-Activity Relationships

A A, B: Bulky groups,
R

B CHAIN N Cycloalkyl, aromatic

R X: H, OH, CONH2
X

Anticholinergic compounds may be considered chemicals that have some
similarity to ACh but contain additionally substituents that enhance their
binding to the cholinergic receptor. .

• The Cationic Head: It is generally considered that the anticholinergic
molecules have a primary point of attachment to cholinergic site through the
cationic head (i.e. the positively charged nitrogen).

For quaternary ammonium compounds, there is no question of what is
implied, but for tertiary amines, one assumes, with good reason, that the
cationic head is achieved by protonation of the amine at physiological pH.

11

A. Muscarinic Antagonists Structure-Activity Relationships

A A, B: Bulky groups,
R

B CHAIN N Cycloalkyl, aromatic

R X: H, OH, CONH2
X

-Steric factor that cause diffusion of the onium charge or produce a less-than-
optimal drug-receptor interaction result in a decrease of parasympathomimetic
properties and allow the drug to act as antagonist because of other bonding
interactions.

Ariens has shown that carbocholines engage in a typical competitive action with
ACh, though they are less effective than the corresponding compounds possessing
a cationic head, suggesting that hydrophobic bonding may play an important role in
these drug-receptor interactions.

12

A. Muscarinic Antagonists Structure-Activity Relationships

A A, B: Bulky groups,
R

B CHAIN N Cycloalkyl, aromatic

R X: H, OH, CONH2
X

– The nitrogen-linked alkyl groups (R) may be greater than methyl (as opposed to
agonists). When N1 groups are ethyl or isopropyl, the effect is maximized but
toxicity is increased.

– Quaternary N can be in the ring {eg; pyridine, piperidine, pyrrolidine). While
agonists have to carry quarternary nitrogen, the antagonist’s nitrogen may be
tertiary or quaternary. However, it should be noted that the tertiary nitrogen atom is
charged when it interacts with the receptor.

•

13

A. Muskarinik Antagonistler Yapı-Aktivite İlişkileri

A A, B: Bulky groups,

B Cycloalkyl, aromatic
Ara zincir N

X: H, OH, CONH2
X

• The Hydroxyl Group :

Not requisite for activity, a suitably placed alcoholic hydroxyl group increases
antimuscarinic activity over that of a similar compound without the hydroxyl
group.

The position of the hydroxyl group relative to the nitrogen appears to be fairly
critical, with the diameter of the receptive area estimated to be about 2 to 3 Ao.

It is assumed that the hydroxyl group contributes to the strength of binding,
probably by hydrogen bonding to an electron-rich portion of the receptore
surface. 14

Yapı-Aktivite İlişkileri

A A, B: Bulky groups,

B Ara zincir N Cycloalkyl, aromatic
X: H, OH, CONH2

X

• The Esteratic group

Many of the highly potent antimuscarinic compounds possess an ester

grouping, and this may be a contributing feature for effective binding.

This is reasonable because the agonist possess a similar function or binding

to the same site.

An esteratic function is not necessary for activity, because several types of

compounds do not possess such a group (e.g., ethers, aminoalcohols).

15

Yapı-Aktivite İlişkileri

A A, B: Bulky groups,

B Ara zincir N Cycloalkyl, aromatic
X: H, OH, CONH2

X

Cyclic substitution :

The active compounds have at least one cyclic substituent (phenyl thienyl, or

other) is a common feature in almost all anticholinergic molecules.

Aromatic substitution is often used in connection with the acidic moiety of the

ester function.

Bulky acids {Mandelic, Tropical, Benzilik, etc.} are required for activity. (Very

large acyl groups may be present (A and B = aromatic or heteroaromatic ring),

This is in contrast to agonists that only acetyl groups are acceptable. 16

II. PARASYMPATOLITIC DRUGS (ANTICHOLINERGICS)
A. Muscarinic Antagonists

Antagonism of muscarinic cholinergic receptor

Effects and uses of muscarinic antagonists

Cholinergic receptor antagonists bind to the receptor but do not activate
receptors.

17

Clinical effects of muscarinic antagonists:

 Antisecretory effect: reduced salivation (antisialagogue), reduced
perspiration (anhidrotic), and reduced acid and gastric secretion

 Antispasmodic effect: lowered tone and motility of the GI tract and the
genitourinary tract

 Mydriatic effect: Dilation of the pupil of the eye

Clinical uses:
 Shutting down digestion for surgery
 Ophthalmic examinations
 Treatment of Parkinson’s disease
 Treatment of anticholinesterase poisoning
 Motion sickness

18

A. Muscarinic Antagonists

Classifications

1. Solanaceous alkaloids and analogues

2. Synthetic cholinergic blocking agents
• Aminoalcohol esters
• Aminoalcohol ethers
• Aminoalcohols
• Aminoamides
• Quaternary amin derivatives
• Miscellaneous
• Papaverine alkaloids and analogues

19

1. Solanaceous alkaloids analogues and its synthetic derivatives
The solanaceous alkaloids, represented by (-)- Atropine ve hyoscine (Scopolamine)
hyoscyamine, atropine, and scopolamine
(hyoscine) are the forerunners of the class of
antimuscarinic drugs. These alkaloids are found
principally in henbane (Hyoscyomus niger),
deadly nightshade (Atropa belladonna).

All of the solanaceous alkaloids are esters of
the bicyclic aminoalcohol.

Solanaceous alkaloids are racemate because
of the asymmetric carbon atom on tropic acid.

The proper enantiomorph is necessary for high antimuscarinic acitivity, as illustrated by
the potent (-) hyoscyamine in comparison with the weakly active (+)-hyoscyamine. .

Solanaceae alkaloids are antimuscarinic. They were used in hemorrhoides because of
their weak local anesthetic effects. They stimulate the respiratory center.
They lead to mydriasis. They commonly use as antispasmodic.

20

Solanaceous alkaloids (the Tropin structures) and their synthetic derivatives

 Atropine
 Hyoscyamine
 Scopolamine HBr
 Homatropine HBr
 Ipratropium Br
 Tiotropium Br
 N-Buthylscopolamine
 Oxytropium bromide

21

Solanaceous alkaloids (the Tropin structures) and their synthetic derivatives

Compound

Atropine
(+/-)-a-(Hydroxymethyl)benzen acetic acid 8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl ester

Hyoscyamine
(-)-a-(Hydroxymethyl)benzen acetic acid 8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl ester

Homatropine
a-Hydroxybenzen acetic acid 8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl ester

Ipratropium bromide
3-(3-Hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-isopropyl-8-
azonazbicyclo[3.2.1]octan bromide 22

Compound

Scopolamine

N-Buthylscopolamine

Oxytropium bromide

23

ATROPINE = TROPINTROPAT
 It is anticholinergic that blocks muscarinic

receptors.

 It competitively binds to muscarinic receptor
and antagonizes it thus blocking all
cholinergic effects

 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 form.

 At therapeutic does it can penetrate the brain
and stimulate the CNS

CH3

N
CH COOH

H

CH2OH
OH

Tropic Acid (a-(hydroxymethyl)- Tropine (8-methyl-8-azabicyclo-[3.2.1]octan-3-ol)
24

benzenacetic acid

Uses:

 Decrease GIT motility

 Treat bradycardia

 Reduce secretion before surgery

 Traet iritis (painful inflammation of eye)
Dilation of eye pupils.

 Organophosphate poisoning (only to
decrease muscarinic action, not an
antidote like PAM) (Antidote for
Anticholinesterase poisoning).

25

Atropine with ACh

• Relative positions of ester and
nitrogen similar in both molecules

• Nitrogen in atropine is ionised

• Amine and ester are important
binding groups (ionic + H-bonds)

• Aromatic ring of atropine is an extra
binding group (vdW)

• Atropine binds with a different
induced fit – no activation

• Atropine binds more strongly than
acetylcholine

26

28

Atropine metabolism;

 Aromatic hydroxylation,

 Ester hydrolysis and then formation of glucuronate through the
alcohol function,

 N-demethylation

31

SCOPOLAMINE ANTIMAREN / ANTINOZAN
It has a stronger effect than atropine. It is used in
painful spasms and motion sickness. In overdose [1
mg], speech disorder, movement and mental
activities decrease.

N-BUTHYLSCOPOLAMINE (Hyoscine-N-buthyl Br); (Buscopan, Buskas,
Buskalgin,Buscotek, Buskoplan, Pankopan, Spazmol, Tranco-Buscopan)

It is a potent anti-spasmodic and semi-synthetic compounds.

Parenteral use is preferred because it is absorbed in a low rate when taken orally.
It is used in GI spasms and especially bile and renal colic.

32

IPRATROPIUM: 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-
8_(1-methylethyl)-8-azoniabicyclo[3.2.1]octane bromide

Ipratropium is a quaternary ammonium derivative of atropine. It is used
to treat the symptoms of chronic obstructive pulmonary disease (COPD)
and asthma. It is used by inhaler or nebulizer. It can not enter the CNS
due to the positive charge in its structure.

33

TROPENZILINE Br PALEROL

H CH
3C 3

N

. Br
6-methoxytropine benzylate methyl bromide

CH3O OC C OH

O

Reduces the motility and tone of the GIT, it has both antispasmodic and analgesic
effect and hence;

-Gastrododuonal ulcer, gastritis, colitis, kidney stone, cystitis, cystopyelitis etc. Used
in gastrointestinal and urogenital spasms,

-Contraindicated: In glaucoma and prostatic hypertrophy patients. for alcohol and
sedatives,

-It makes sedation. Therefore, person who work in high places and driving sho34uld
be warned.

2. Synthetic cholinergic blocking agents
• Aminoalcohol Esters

They are used as an antispasmodic, mydriatic ve antiparkinson.

Another important feature in many of the synthetic anticholinergic used as
antispasmodics is that they contain a quaternary nitrogen, presumably to enhance
activity.

These compounds combine anticholinergic activity of the antimuscarinic type with
some ganglionic blockade.

35

2. Synthetic cholinergic blocking agents
• Aminoalcohol Esters

• Clidinium Bromide
• Cyclopentolate Hydrochloride
• Dicyclomine Hydrochloride
• Eucatropine Hydrochloride
• Mepenzolate Bromide
• Oxyphencyclimine Hydrochloride
• Glycopyrrolate
• Methantellin
• Propantheline Bromide

36

Clidinium Bromide LIBRAX PRODARTAL

OH

C C O
. Br N-methyl-3-quinuclidinyl-benzilate bromide

O
N

CH3

– The anticholinergic agent is marketed alone and in combination with the minor
tranquilizer chlordiazepoxide (Librium) in a product known as Librax. The rationale of
the combination for the treatment of GI complaints is the use of an anxiety-reducing
agent together with an anticholinergic agent, based on the recognized contribution of
anxiety to the development of the diseased condition.

– It is suggested for peptic ulcer, ulcerative or spastic colon, anxiety states with GI
manifestations, nervous stomach, irritable or spastic colon and others.

– Clidinium bromide is contraindicated in glaucome and other conditions that may be
aggravated by the parasympatholytic action, such as prostatic hypertrophy in elderl3y7
men, which could lead to urinary retention.

Cyclopentolate SİKLOMİD, SİKLOPLEJİN

It is used only for its effects on the eye, where it acts as a parasympatholytic. When it drops
in the eye, it quickly produces cycloplegia and mydriasis. The effect ends in a short time,
does not irritate the eyes.

Synthesis

(RS)-2-Dimethylaminoethyl-1-hydroxy-α-phenylcyclopentaneacetate

38

Dicyclomine Hydrochloride

It is used to treat the symptoms of irritable bowel syndrome (a disorder in large intestine that causes
cramping, abdominal pain, bloating, gas), specifically hypermotility, in adults.

It is used for its spasmolytic effect on various smooth muscle spasm, particularly those associated
with the GI tract as an oral or parenteral.

Synthesis

2.

1.

2-Diethylaminoethyl-1-cyclohexyl-cyclohexancarboxylate
39

Oxyphencyclimine DARİCON, AN-KOL

1,4,5,6-Tetrahydro-1-methyl-2-pyrimidinyl)methyl a-phenylcyclohexaneglycolate

It is used as antispasmodic. It is absorbed from the GI tract and has a duration of action of up to 12
hours.

40

Methantheline Br

Diethyl(2-hydroxyethyl)methylammonium bromide xanthene-9-carboxylate

It has a xanthene ring in its structure. It has an more potent antispasmodic effect than atropine. It
has a ganglio blocker effect.

Side reactions are atropine-like (mydriasis, cycloplegia, dryness of mouth). The drug is
contraindicated in glaucoma. Toxic doses may bring about a curar-like action, a not too suprising
fact when it is considered that ACh is the mediating factor for neural transmission at the somatic
myoneural junction. This side effect can be counteracted with neostigmine methylsulfate.
Propantheline can be preferred.

41

Propantheline Bromide BANTİNOVA

(2-Hydroxy-ethyl)diisopropylmethylammonium
bromide xanthene-9-carboxylate

Its chief difference from methantheline bromide is in its
potency, which has been estimated variously to be 2 to 5 times
as great.. Strongly inhibits tonus and motility in the
gastrointestinal tract. So, it is used in peptic ulcer and gastritis
(reduces gastric acid secretion)

The inhibitory effect of the stomach on acid secretion is also
very strong. In addition, a single dose of [15-20 mg] is used
against enuresis nocturia.

42

Mepenzolate Bromide

 It has an activity about one
half that of atropine in
reducing ACh induced
spasms of the ileum.

 The selective action on
colonic hypermotility is said

N-Methyl-3-piperidyl-benzilate methyl bromide
to relieve pain, cramps,
and bloating and to help
curb diarrhea.

43

Adiphenine SPAZMO-PANALGINE

C2H5
Diphenylacetic acide-2-diethylamino-ethylester ;HCl

CH C O CH2CH2N
C2H

O 5

It is used to treat spasm and peptic ulcer. While its spasmolytic effect is 25 times
stronger than atropine, it has the same level of spasmodic effect as papaverine

44

Quaternary amine derivatives;

OH C2H5

Oxyphenonium Br ANTRENYL C C O CH2CH2N CH.3 Br

O C2H5

2-(2-Cyclohexyl-2-hydroxy-2-phenylacetoxy)-N,N-diethyl-
N-methyl ethanammonium bromide

It is an antimuscarinic drug. It is used to treat peptic ulcer and gastric hypermotility

Contraindicated: In Glaucome, prostat hypertrophy.

Side effect: Dry mouth, visual impairment, dizziness

Synthesis ; OH
OH C

C 2H5
2H5

C COOCH3 C C O CH2CH2N
NaOCH3

+ HO CH2CH2N O C2H5

C2H5

OH C2H5

C C O CH2CH2N CH3 . Br
CH3Br

O C2H5
45

OH

Pipenzolate methyl bromide PIPTAL C C O
. Br

O
N-Ethyl-3-piperydinyl benzilate methyl bromide N

H3C C2H5

Pipenzolate bromide is an antimuscarinic. It binds to muscarinic acetylcholine
receptors as an antagonist therefore preventing ACh from binding to the receptors. It
is used flatulent dyspepsia, infantile colics.

-Side effects: Urinary stiffness, constipation and blurred vision

OH Cl OH

Synthesis ; C COOH C C O

+ O
N N

C 2H
2H C 5

5

OH

C C O
. Br

O
N

H3C C2H5 46

Hexocyclium Methylsulfate TRAL TRALIN

4-(2-cyclohexyl-2-phenyl-2-hydroxyethyl)-1,1-
OH dimethyl piperazinium methyl sulfate

C CH3
.

CH H S
2 N N C 3 O4

CH3

Anticholinergic

O
Synthesis:

C CH3
O

+ Cl N N CH3 C CH2 N N CH3

OH OH

MgBr C
(CH3)2SO4 C CH3

CH2 N N CH .
3 CH2 N N CH3SO4

CH3

47

Flavoxate-HCl URISPAS

3-Methyl-4-oxo-2-phenyl-4H-1-benzopiron-
8-carboxylic acide-2-piperidino-ethyl ester

8-(2-piperidino-ethyl)-3-methyl-4-oxo-2-phenyl-4H-1-
benzopiron-8-carboxylate

Urinary system antispasmodic

48

• Aminoalcohol ethers

The aminoalcohol ethers thus far introduced have been used as antiparkinsonian drugs rather than
as conventional anticholinergics (spasmolytics or mydriatics) In general, they may be considered
closely related to the antihistaminics and, indeed, do possess substantial antihistaminic properties.

Benzotropine mesylate Chlorphenoxamine
8-Methyl-8-azabicyclo[3.2.1]oct-3-yl benzhydryl ether [1-(p-chlorophenyl)-1-phenyl]ethyl (2-dimethylaminoethyl)ether
methanesulfonate

Orphenadrine citrate
N,N-dimethylaminoethyl-2-methylbenzhydryl
ether

49

Benzotropine mesylate

8-Methyl-8-azabicyclo[3.2.1]oct-3-yl benzhydryl ether
methanesulfonate

 Benzotropine mesylate has anticholinergic, antihistaminic, and local
anesthetic properties.

 Its anticholinergic effect makes it applicable as an antiparkinsonian agent.

 It is about potent an anticholinergic as atropine and shares some of the side
effects of this drug, such as mydriasis and dryness of mouth.

50

Orphenadrine citrate

N,N-dimethylaminoethyl-2-methylbenzhydryl ether

 Orphenadrine citrate, is closely related to diphenhydramine structurally but
has much lower antihistaminic activity and much higher anticholinergic
action.

 Likewise, it lacks the sedative effects characteristic of diphenhydramine.

 Pharmacological testing indicates that it is not primarily a peripherally acting
anticholinergic because it has only weak effects on smooth muscle, on the
eye, and on secretory glands.

 It does reduce voluntary muscle spasm, however, by a central inhibitory
51

action on cerebral motor areas, a central effect similar to that of atropine.

Synthesis of chlorphenoxamine:

Cl Cl

p-Chloroacetophenon

[1-(p-chlorophenyl)-1-phenyl]ethyl (2-dimethylaminoethyl)ether

52

2. Synthetic cholinergic antogonists
• Aminoalcohols Formula

Biperiden
a-Bicyclo[2.2.1]hept-5-en-2-yl-a-phenyl-1-piperidinylpropanol

Antispasmodic.

Its used in Procyclidine
1-Cyclohexyl-1-phenyl-3-pyrrolidinepropanol

Parkinson’s disease
for eliminating
akinesia, rigidity, and
tremor.

Tridihexetyl iodide
(3-Cyclohexyl-3-hydroxy-3-phenylpropyl)triethylammonium
iodide

Trihexyphenidyl
1-Cyclohexyl-1-phenyl-3-piperidinylpropanol

53

• Aminoamides

Isopropamide iodide

2,2-Diphenyl-4-diisopropylaminobutyramide methyl iodide

 This drug is a potent anticholinergic, producing atropine-like
effects peripherally.

 It is used as adjunctive therapy in the treatment of peptic ulcer and
other conditions of the GI tract associated with hypermotility and
hyperacidity. 54

Tropicamide MIDRIACYL

N-Ethyl-a-(hydroxymethyl)-N-(4-pyridylmethyl)benzeneacetamide

It is an effective anticholinergic for ophthalmic use when mydriasis is produced by relaxation
of the sphincter muscle of the iris. Its maximum effect is achieved in about 20 to 25 minutes
and lasts for about 20 minutes, with complete recovery in about 6 hours.

55

Fenprevinium Br BARALGINE

It is an anticholinergic and antispasmodic. It is marketed as a
CH3

O combination drug with pitofenone_HCl and either nimesulide or
N

CH2CH2 C C NH Br metamizole to treat smooth muscle spasms and pain.
2

2,2-Diphenyl-4-(1-methyl-piperidinium)butyramide-bromide

Sentezi:

HC CN + NCH2CH2Cl NaNH2 N CH2CH2 C CN

Diphenylacetonitrile 1)H2SO4

CH 2)NH
3 3

O
N 3) CH3Br

CH B
2CH2 C C NH r

2

56

Pirenzepine GASTROZEPIN

O

C CH2 N N CH3

N N

N

O

5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido-[2,3-b] [1,4] benzodiazepine-6-
one

Pirenzepine, which includes tricyclic structure, is gastro-selective. It was
found to be close to Histamine H2 receptore blockers in the treatment of
peptic ulcer. Selective M1 antagonist.

Decreases gastric acid secretion – promotes ulcer healing

57

• Miscellaneous

Diphemanil methylsulfate

4-(Diphenylmethylene)-1,1-dimethylpiperidinium
methylsulfate

It is a potent anticholinergic compound. It is useful in the treatment of peptic ulcer,
hypermotility and acidity

58

Synthesis of Diphemanil methylsulfate

59

Ethopropazine

10-[2-(diethylaminopropyl)]phenothiazine

Especially useful in the symptomatic treatment of parkinsonism.

60

• Papaverine alkaloids and synthetic derivatives

Papaverine is an isoquinoline derivative. Its main effect is as a spasmolytic on smooth muscle, acting as a
direct, nonspecific relaxant on vascular, cardiac, and other smooth muscle.

Compound

Papaverine
6,7-Dimethoxy-1-veratrylisoquinoline

Etaverine
1-(3,4-Diimethoxybenzyll)-6,7-diiethoxyiisoquiinolliine

61