cholinergic agents as per PCI syllabus

1. AS PER PCI SYLLABUS
B PHARMACY FOURTH SEMESTER
By: Somashekhar M Metri
Weser Books Publishers, Germany

2. Chapter 3.Cholinergic Agents
Cholinergic neurotransmitters: Biosynthesis and catabolism of acetylcholine. Cholinergic
receptors (Muscarinic & Nicotinic) and their distribution, Parasympathomimetic agents: SAR of
Parasympathomimetic agents. Direct acting agents: Acetylcholine, Carbachol*, Bethanechol,
Methacholine, Pilocarpine. Indirect acting/ Cholinesterase inhibitors (Reversible & Irreversible):
Physostigmine, Neostigmine*, Pyridostigmine, Edrophonium chloride, Tacrine hydrochloride,
Ambenonium chloride, Isofluorphate, Echothiophate iodide, Parathione, Malathion.
Cholinesterase reactivator: Pralidoxime chloride. Cholinergic Blocking agents: SAR of
cholinolytic agents. Solanaceous alkaloids and analogues: Atropine sulphate, Hyoscyamine
sulphate, Scopolamine hydrobromide, Homatropine hydrobromide, Ipratropium bromide*.
Synthetic cholinergic blocking agents: Tropicamide, Cyclopentolate hydrochloride, Clidinium
bromide, Dicyclomine hydrochloride*, Glycopyrrolate, Methantheline bromide, Propantheline
bromide, Benztropine mesylate, Orphenadrine citrate, Biperidine hydrochloride, Procyclidine
hydrochloride*, Tridihexethyl chloride, Isopropamide iodide, Ethopropazine hydrochloride.

3. INTRODUCTION
•Acetylcholine is an organic molecule that acts as a neurotransmitter in many organisms, including humans.
•It is an ester of acetic acid and choline, Acetylcholine is one of many neurotransmitters in the autonomic nervous
system (ANS).
•It acts on both the peripheral nervous system (PNS) and central nervous system (CNS) and is the only neurotransmitter used
in the motor division of the somatic nervous system. Acetylcholine is also the principal neurotransmitter in all autonomic
ganglia.
•In cardiac tissue acetylcholine neurotransmission has an inhibitory effect, which lowers heart rate.
•However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions in skeletal muscle.
Function
•Acetylcholine has functions both in the peripheral nervous system (PNS) and in the central nervous system (CNS) as a
neuromodulator.
•Its receptors have very high binding constants.
•In the peripheral nervous system, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous
system.
•In the central nervous system, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic
system, which tends to cause anti-excitatory actions.
In the peripheral nervous system
•In the peripheral nervous system, acetylcholine activates skeletal muscles, and is a major neurotransmitter in the autonomic
nervous system.
•Acetylcholine binds to acetylcholine receptors on skeletal muscle fibers; it opens ligand-gated sodium channels in the cell
membrane.
•Sodium ions then enter the muscle cell, initiating a sequence of steps that finally produce muscle contraction. Although
acetylcholine induces contraction of skeletal muscle, it acts via a different type of receptor (muscarinic) to inhibit contraction
ofcardiac muscle fibers.
In the autonomic nervous system
In the autonomic nervous system, acetylcholine is released in the following sites:
•All pre- and post-ganglionic parasympathetic neurons
•All preganglionic sympathetic neurons.
•The suprarenal medullae are modified sympathetic ganglia. On stimulation by acetylcholine, the suprarenal medulla
releases epinephrine and norepinephrine.

4. In the autonomic nervous system
In the autonomic nervous system, acetylcholine is released in the following sites:
•All pre- and post-ganglionic parasympathetic neurons
•All preganglionic sympathetic neurons.
•The suprarenal medullae are modified sympathetic ganglia. On stimulation by acetylcholine, the suprarenal
medulla releases epinephrine and nor-epinephrine.
•Sudomotor neurons to sweat glands.
In the central nervous system
•In the central nervous system, ACh has a variety of effects as a neuromodulator upon plasticity, arousal
and reward.
•ACh has an important role in the enhancement of sensory perceptions when we wake upand in sustaining
attention.
•Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly
associated with the memory deficits associated with Alzheimer's disease.
•ACh has also been shown to promote REM sleep. Recently, it has been suggested that acetylcholine
disruption may be a primary cause of depression.
•When ACh was first demonstrated in the frog heart in 192I by Loewi as the substance released by vagus
nerve stimulation the drugs and chemicals that act on cholinergic nerves or the tissues they innervate to either
mimic or block the action of ACh.
•Drugs that mimic the action of ACh do so either by acting directly on the cholinergic receptors in the tissue
or by inhibiting acetylchnlinesteruse (AChE), the enzyme that inactivates ACh at the nerve terminal.
•Chemicals that bind or compete with ACh for binding to the receptor may block cholinergic
neurotransmission.

5. •The synthesis of ACh in the varicosity depends on the uptake of choline via a sodium-dependent carrier.
•This uptake can be blocked by hemicholinium. Choline and the acetyl moiety of acetyl coenzyme A, derived
from mitochondria, form ACh, a process catalyzed by the enzyme choline acetyltransferase (ChAT).
•ACh is transported into the storage vesicle by another carrier that can be inhibited by vesamicol
acetylcholine
O
N
+ CH3
CH3
CH3
O
CH3 + H2O
Acetylcholine Esterase
Acetate
CH3
O
O
-
Choline
OH
N
+ CH3
CH3
CH3+ +H
+
•ACh is stored in vesicles along with other potential co-transmitters (Co-T) such as ATP. at certain
neuroeffector junctions.
•Release of ACh and the Co-T occurs on depolarization of the varicosity, which allows the entry of Ca2+
through voltage-dependent Ca2+ channels.

6. Schematic representations of a cholinergic neuroeffector junction showing features of the synthesis,
storage, and release of acetylcholine (ACh) and receptors on which ACh acts

7. •Elevated [Ca2+] in promotes fusion of the vesicular membrane with the cell membrane, and exocytosis of the
transmitters occurs.
•This fusion process involves the interaction of specialized proteins associated with the vesicular membrane
(VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-
associated proteins).
•The exocytotic release of ACh can be blocked by botulinum toxin. Once released, ACh can interact with the
muscarinic receptors (mAChR), which are GPCRs, or nicotinic receptors (nAChR), which are ligand-gated
ion channels, to produce the characteristic response of the effector.
•ACh also can act on presynaptic mAChRs or nAChRs to modify its own release. The action of ACh is
terminated by metabolism to choline and acetate by acetylcholinesterase (AChE), which is associated with
synaptic membranes.
Storage of Acetylcholine
•After its synthesis from choline, ACh is taken up by the storage vesicles principally at the nerve terminals.
•The vesicles are transported from the cell body via the microtubules, with little ACh incorporation taking
place during this process.
•There appear to be two types of vesicles in cholinergic terminals: electron-lucent vesicles (40 to 50 nm in
diameter) and dense-cored vesicles (80 to 150 nm).
•The core of the vesicles contains both ACh and ATP, at an estimated ratio of 10:1, which are dissolved in the
fluid phase with metal ions (Ca2+ and Mg2+) and a proteoglycan called vesiculin.
•Vesiculin is negatively charged and is thought to sequester the Ca2+ or ACh. It is bound within the vesicle,
with the protein moiety anchoring it to the vesicular membrane.
•In some cholinergic terminals there are peptides, such as VIP, that act as co-transmitters at some junctions.
•The peptides usually are located in the dense-cored vesicles. Vesicular membranes are rich in lipids,
primarily cholesterol and phospholipids, as well as protein.
•The proteins include ATPase, which is sensitive and thought to be involved in proton pumping and in
vesicular inward transport of Ca2+.

8. Release of Acetylcholine
•The motor end plate of skeletal muscle and observed the random occurrence of small (0.1 to 3.0 mV)
spontaneous depolarization’s at a frequency of approximately 1 Hz.
•The magnitude of these maps is considerably below the threshold required to fire a muscle action potential
(AP); that they are due to the release of ACh is indicated by their enhancement by neostigmine (an anti-ChE
agent) and their blockade by D -tubocurarine (a competitive antagonist that acts at nicotinic receptors).
•These results led to the hypothesis that ACh is released from motor nerve endings in constant amounts, or
quanta.

9. Cholinergic receptors
•Sir Henry Dale noted that the various esters of choline elicited responses that were similar to those of either
nicotine or muscarine depending on the pharmacological preparation.
•A similarity in response also was noted between muscarine and nerve stimulation in those organs innervated
by the craniosacral divisions of the autonomic nervous system.
•Thus, Dale suggested that ACh or another ester of choline was a neurotransmitter in the autonomic nervous
system; he also stated that the compound had dual actions, which he termed a "nicotine action" (nicotinic)
and a "muscarine action" (muscarinic).
•Not all cholinergic receptors are identical
•Two types of cholinergic receptor - nicotinic and muscarinic
•Named after natural products showing receptor selectivity
N
N
CH3
3-(1-methylpyrroli
din-2-yl)pyridine
Nicotine
•Activates cholinergic receptors at nerve synapses and on skeletal muscle
O
N
+CH3
CH3
CH3
CH3
OH
(4-hydroxy-5-methyltetrahydrofu
ran-2-yl)-N,N,N-trimethylmethan
aminium
Muscarine
•Activates cholinergic receptors on smooth muscle and cardiac muscle
•There are two distinct receptor types for ACh that differ in composition. Location and pharmacological
functional have specific agonists and antagonists.

10. •Cholinergic receptors have been characterized as, nicotinic and muscarinic on the basis of their ability to be
bound by the naturally occurring alkaloids nicotine and muscarinic respectively.
•Receptors subtypes that differ in location and specificity to agonist and antagonists have been identified for
both the nicotinic and muscarinic receptors.
Cell
membrane
Five glycoprotein subunits
traversing cell membrane
Receptor
Binding
site Messenger
Cell
membrane
Induced
fit
‘Gating’
(ion channel
opens)

11. a
a
g
d
b
Two ligand binding sites
mainly on a-subunits
Ion channel
2xa, b, g, d subunits
Binding
sites
Cell
membrane
a
ad
b
g

12. Nicotinic receptors: nicotinic ach receptors are found at the skeletal neuromuscular junction, adrenal
medulla, and autonomic ganglia. The important role they play in myasthenia gravis, autoimmune disease.
closed
messenger
induced
fit
open
G-protein
bound
G-protein
split

13. active site
(closed)
active site
(open)
Enzyme Enzyme
Intracellular
reaction
subunit

15. Characteristics of subtypes of nicotinic acetylcholine receptors
Receptor
Subtypes
Location Mechanism Agonists Antagonists
NM
Skeletal Muscle
Skeletal
Neuromuscular
Junction
Increased Ach
cation
permeability
(Na+ k+)
Acetylcholine Atracurium
d-Tubocurarine
NN
Peripheral
Neuronal
Autonomic
Ganglia
Adrenal Medulla
Increased Ach
cation
permeability
(Na+ k+)
Acetylcholine Trimethaphan
Mecamylamine
d-Tubocurarine

16. Muscarinic acetylcholine receptors
•Muscarinic acetylcholine receptors in the peripheral nervous system are found primarily on autonomic
effector cells innervated by postganglionic parasympathetic nerves.
•Muscarinic receptors also are present in ganglia and on some cells, such as endothelial cells of blood vessels
that receive little or no cholinergic innervation. Within the central nervous system (CNS), the hippocampus,
cortex, and thalamus have high densities of muscarinic receptors.
Receptor subtypes Location Mechanism Function
M1
Cerebral cortex
Autonomic Ganglia
Salivary glands
Activation of IP3
Increase Ca++
Increased Cognitive function
(learning and memory)
Decrease dopamine release and
and locomotion
Increase in secretions of heart
M2
CNS, Heart
Smooth Muscles
Autonomic nerve terminal
Inhibition of Adenylyl cyclase
Decrease cAMP
SA node Slow
AV node decrease in conduction
conduction velocity
M3
CNS, Heart
Smooth Muscles
Glands
Activation of IP3
Increase Ca++
Increase smooth muscle
Increase contraction
Increase food intake
Increase body weight
M4
Forebrain Inhibition of Adenylyl cyclase
Decrease cAMP
Auto receptor and hetero receptor
receptor mediated inhibition
transmitter release in CNS and
Periphery
M5
Low levels of Brain Activation of IP3
Increase Ca++
Increase dilation of cerebral
arteries and arterioles
Augmentation of drug seeking
behavior and reward

17. Direct acting agents: Acetylcholine, Carbachol*, Bethanechol, Methacholine, Pilocarpine.
These drugs directly bind and activate nicotinic and muscarinic receptors with variable amounts of
selectivity.

18. •Bethanechol is used to treat urinary retention (difficulty urinating), which may occur after surgery, after
delivering a baby, and in other situations. Bethanechol may also be used for purposes other than those listed
in this medication guide.
•Methacholine is not recommended for use if you already have asthma, wheezing, or poor lung function test
results before this challenge test. Methacholine is used as a test to determine whether you may have asthma.
It is a cholinergic drug that causes wheezing and shortness of breath.
•Pilocarpine is used to treat symptoms of dry mouth due to a certain immune disease (Sjogren's syndrome) or
from saliva gland damage due to radiation treatments of the head/neck for cancer. Pilocarpine belongs to a
class of drugs known as cholinergic agonists.

19. Indirect acting/ Cholinesterase inhibitors (Reversible & Irreversible)
Physostigmine, Neostigmine*, Pyridostigmine, Edrophonium chloride, Tacrine hydrochloride,
Ambenonium chloride, Isofluorphate, Echothiophate iodide, Parathione, Malathion.
Cholinesterase reactivator: Pralidoxime chloride.
•Cholinergic transmission involves the neurotransmitter acetylcholine being released from nerve
fibers, binding to designated receptors on other cholinergic nerve fibers and passing on the
message to bring about a response.
•Cholinesterase enzymes are present in the synaptic cleft of cholinergic synapses, and they
hydrolyze acetylcholine, decreasing its concentration in the synapses.
•Cholinesterase inhibitors bind to cholinesterase resulting in increased acetylcholine in the
synapses, causing increased parasympathetic activity i.e. vasodilatation, constriction of pupils in
the eyes, increased secretion of sweat, saliva and tears, slow heart rate, mucus secretion in the
respiratory tract and constriction of bronchioles and so on.
•The cholinesterase inhibitors listed here are mainly ones that affect the central nervous system.
•They penetrate the blood brain barrier and enhance cholinergic transmission in the brain. These
agents are used to treat dementia in patients with Alzeihmer.

20. Physostigmine Dose: Topical, for open-angle glaucoma, 0.1 ml of a 0.25 to 5% solution instilled into the conjunctival sac 2 or 4 times daily
Dose: Initially, 60 mg every 4 to 8 hours, but 120 to 300 mg 6 times daily is the usual dose.

21. Irreversible Inhibitors
•Both AChE and BuChE are inhibited irreversibly by group of phosphate esters that are highly toxic (LD50
for humans is 0.1 to 0. (X) l mg/kg). These chemicals are nerve poisons and have been used in warfare, in
bioterrorism and as agricultural insecticides.
•They permit ACh to accumulate at nerve endings and exacerbate ACh-like actions. The compounds belong
to a class of organophosphorous esters.
Malathion
•It is a water-insoluble phosphodithioate ester that has been used as an agricultural insecticide.
•Malathion is a poor inhibitor of cholinesterases. Its effectiveness as a safe insecticide is due to the different
rates at which humans and insects metabolize the chemical.
Parathion
•Parathion is used as an agricultural insecticide. It is a relatively weak inhibitor of cholinesterase: however,
enzymes present in liver microsomes and insect tissue converts parathion to paraoxon.

22. •A more potent inhibitor of cholinesterase Parathion is also metabolized by liver microsomes to yield p-
nitrophenol and diethylphosphate; the latter is inactive as an irreversible cholinesterase inhibitor.
N
+
O
O
-
O
P
S O
CH3
O
CH3
{4-[(diethoxyphosphorot
hioyl)oxy]phenyl}(hydrox
y)oxoammonium
(Parathion)
N
+
O
O
-
O
P
O O
CH3
O
CH3
(Paraxon)
N
+
O
O
-
OHP S
O
CH3
O
CH3
OH +
O,O-diethyl
hydrogen
phosphorothioate
hydroxy(4-hydroxyph
enyl)oxoammonium
Cholinesterase reactivator:
•The use of pesticides allows human to stabilize and increase agricultural production
•Among various types of pesticides, the organophosphorus pesticides (OPP) are targeted to the insect
elimination.
•They were developed as esters of phosphonic or phosphoric acid or their thio-analogues e.g. paraoxon,
chlorpyriphos, diazinon, dimethoate
•Their mechanism of action consists in the irreversible inhibition of cholinesterases in the insect body,
namely acetylcholinesterase (AChE) or butyrylcholinesterase (BChE).
• The cholinesterases irreversible inhibition is based on formation of covalent bond between OPP and serine
moiety in the AChE active site.

23. •The AChE is responsible for termination of neuronal transmission via degradation of acetylcholine in the
synaptic cleft.
•This irreversible AChE inhibition causes the accumulation of acetylcholine in the synaptic cleft and thus
permanent activation of cholinergic (muscarinic or nicotinic) receptors.
•The disrupted neuronal transmission causes the insect death.
Pralidoxime chloride
•Pralidoxime is typically used in cases of organophosphate poisoning. Organophosphates such as sarin bind
to the hydroxy component (the esteric site) of the active site of the acetylcholinesterase enzyme, thereby
blocking its activity.
•Pralidoxime binds to the other half (the unblocked, anionic site) of the active site and then displaces the
phosphate from the serine residue. The conjoined poison / antidote then unbind from the site, and thus
regenerate the fully functional enzyme.
•Dose: Adults: 30 mg/kg (typically 1-2 g), administered by intravenous therapy over 15–30 minutes, repeated
60 minutes later. It can also be given as a 500 mg/h continuous IV infusion. Children: 20–50 mg/kg followed
by a maintenance infusion at 5–10 mg/kg/h.
Cholinergic blocking agents:
Cholinergic Blocking agents: SAR of cholinolytic agents. Solanaceous alkaloids and analogues: Atropine
sulphate, Hyoscyamine sulphate, Scopolamine hydrobromide, Homatropine hydrobromide, Ipratropium
bromide*.

24. •Cholinergic antagonist is a general term for agents that bind to cholinoceptors (muscarinic or nicotinic) and
prevent the effects of acetylcholine (ACh) and other cholinergic agonists. The most clinically useful of these
agents are selective blockers of muscarinic receptors.
•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
•Atropine binds with a different induced fit - no activation
•Atropine binds more strongly than acetylcholine

25. Parasympathetic postganglionic blocking agents:
•An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and
the peripheral nervous system.
•Anti-cholinergics inhibit parasympathetic nerve impulses by selectively blocking the binding of the
neurotransmitter acetylcholine to its receptor in nerve cells.
•The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth
muscles present in the gastrointestinal tract, urinary tract, lungs, etc.
•Anti-cholinergics are divided into three categories in accordance with their specific targets in the central
and/or peripheral nervous system: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers.
Antimuscarinic agents may be classified on the basis of their chemical structures under the following
heads:
•Aminoalcohol Esters. Ex Atropine ,Clidinium
•Aminoalcohol Ethers. Ex Benztropine
•Aminoalcoholcarbamates.
•Aminoalcohols.
•Aminoamides.
•Diamines.
•Miscellaneous Amines.
•Parasympathetic postganglionic blocking agents arc also known as antimuscarinic. Or anticholinergic.
parasympatholytic, or cholinolytic drugs.
•Atropine Dose: Usual, 0.25 mg thrice daily normally taken 30 minutes before meals.
Synthetic cholinergic blocking agents:
Synthetic cholinergic blocking agents: Tropicamide, Cyclopentolate hydrochloride, Clidinium bromide,
Dicyclomine hydrochloride*, Glycopyrrolate, Methantheline bromide, Propantheline bromide, Benztropine
mesylate, Orphenadrine citrate, Biperidine hydrochloride, Procyclidine hydrochloride*, Tridihexethyl
chloride, Isopropamide iodide, Ethopropazine hydrochloride.

26. •One of the muscarinic antagonists with pharmacologic action similar to atropine and used mainly as an
ophthalmic parasympatholytic or mydriatic
•Clidinium inhibits muscarinic acetylcholine
receptors on smooth muscles, secretory glands,
and in the central nervous system to relax
smooth muscle and decrease biliary
tract secretions.
•Dicyclomine hydrochloride behaves both as an anti-muscarinic and a nonspecific antispasmodic agent. It is
frequently employed in the treatment of irritable colon, spastic colitis, mucous colitis, spasticconstipation and
biliary dyskinesia. It also finds its use in the diagnosis of peptic ulcer by delayinggastric emptying process.
•Dose: Oral or intramuscular, 10 to 20 mg after 4 to 6 hours per day.

27. •Glycopyrrolate is a synthetic anti-cholinergic agent with a quaternary ammonium structure.
•A muscarinic competitive antagonist used as an antispasmodic, in some disorders of the gastrointestinal
tract, and to reduce salivation with some anesthetics.
•Propantheline is one of a group of antispasmodic medications which work by blocking the action of the
chemical messengeracetylcholine, which is produced by nerve cells, to muscarinic receptors present in
various smooth muscular tissues, in places such as the gut, bladder and eye.
•Normally, the binding of acetylcholine induces involuntary smooth muscular contractions.

28. •Orphenadrine is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to
diphenhydramine.
•It is used to treat muscle pain and to help with motor control in Parkinson's disease, but has largely been
superseded by newer drugs.
•Procyclidine. Procyclidine is an anticholinergic drug principally used for the treatment of drug-induced
Parkinsonism, akathisia and acute dystonia; Parkinson disease; and idiopathic or secondary dystonia.

29. •Tridihexethyl (which is commonly used as its chloride salt, tridihexethyl chloride) is
an anticholinergic, antimuscarinic andantispasmodic drug.
•It may be used, usually in combination with other drugs, to treat acquired nystagmus or peptic ulcer disease.
Many patients discontinue the drug because of unwanted side effects.
•It is also known as Pathilon or Propethonum.
•Profenamine also known as ethopropazine is a phenothiazine derivativeused as an antiparkinsonian agent.
•That has anticholinergic, antihistamine, and antiadrenergic actions. It is also used in the alleviation of
the extra pyramidal syndrome induced by drugs such as other phenothiazine compounds, but, like other
compounds with anti-muscarinic properties is of no value against tardive dyskinesia.

30. SYNTHESIS
Carbachol
Cl
OH
+
O
Cl2
Cl
O O
Cl
NH3
Cl
O O
NH2
N CH3
CH3
CH3
O O
Cl
N
+
CH3
CH3
CH3
Cl
-
2-chloroethanol Phosgene 2-chloroethyl
carbonochloridoate
2-chloroethy
l carbamate
N,N-dimethy
lmethanamin
e
2-[(chlorocarbonyl)oxy]-N,N,
N-trimethylethanaminium
Carbachol
Neostigmine
OHN
CH3
CH3
+
Cl
O
N
CH3
CH3
O
N
CH3
CH3
O
N CH3
CH3
(CH3O)2SO2
O
N
+
CH3
CH3
O
N CH3
CH3CH3
CH 3OSO3
3-(dimethylamino)
phenol
dimethylcarba
mic chloride
3-(dimethylamino)phe
nyl dimethylcarbamate
3-[(dimethylcarbamoyl)o
xy]-N,N,N-trimethylanili
nium
Dimethyl sulphate
(Neostigmine)

31. N
CH3
H
OH
2-methyl-2-azatric
yclo[5.2.0.01,3]no
nan-5-ol
+
OH
O
OH
3-hydroxy-2-pheny
lpropanoic acid
ClH
N
CH3
H
O
O
OH
2-methyl-2-azatricyclo[5.2.0.01,3]non-5-
yl 3-hydroxy-2-phenylpropanoate
(CH3)2CHBr
2-bromopropane
N
+
H
O
O
OH
CH3
CH3
CH3
Br
-
Ipratropiumbromide
CN
+ Br Br
CN
C2H5OH/H
+
COOC 2H5
OH
N
CH3
CH3
O
O
N
CH3
CH3
H2
O
O
N
CH3
CH3
phenylacetonitrile
1,5-dibromopentane
1-phenylcyclohex
anecarbonitrile
ethyl
1-phenylcycloh
exanecarboxylat
e
2-(diethyl
amino)eth
anol2-(diethylamino)ethyl 1-phenylcyclohexanecarboxylate
Dicyclomine
Ipratropium bromide
Dicyclomine

32. CN
CN
C2H5OH/H
+ COOC 2H5
OH
N
CH3
CH3
O
O
N
CH3
CH3
2-(diethylamino)ethanol
Dicyclomine
+
Br
cyclohexanecar
bonitrile
bromocyclo
hexane
ethyl
1,1'-bi(cycl
ohexyl)-1-c
arboxylate
Procyclidine
O CH3
+ H
O
+
NH Mannich
Reaction
O
N
Grignard
Reagent
BrMg
N
OMgBr
HydrolysisClH
N
+
OH
H
Cl
-
1-phenylet
hanone
formal
dehyd
e
pyrrolidine
1-phenyl-3-(py
rrolidin-1-yl)pr
opan-1-one
Procyclidine