Drugs Acting on the Autonomic

Nervous System

1
 Nervous system
 Nervous system: divided in to two anatomical divisions

– CNS (brain & spinal cord)

– PNS (neurons located outside the CNS & enter or leave the CNS

 PNS divided into two

 Efferent division (motor)

– Carry signal away from CNS

 Afferent division (sensory)

– Bring information from the periphery to the CNS

2
 Nervous system…
 Efferent division falls in to two
 Somatic efferent system

• Controls voluntary functions (skeletal muscles in locomotion)

 Autonomic efferent system:
• its activities are not under direct conscious control
• Involeved in involuntary activities and innervates all smooth
muscles in the body, all the glandular structures & myocardium
(specialized & non specialized)

3
4
 Nervous system…
 An individual nerve cell is called a neuron
 Neurons must communicate with each other in order to relay
messages
 However, neurons are not physically connected
 Instead, there are gaps which are called synapses/ganglia
 If a neuron is to communicate its message to another neuron (or a
target organ), it can only do so by releasing a chemical that crosses
the synaptic gap and binds to receptors on the target cell
Neurotransmitters

5
 Ganglia an aggregation of
nerve cell bodies located in the
peripheral nervous system

function as relay stations

between the preganglionic neuron
and the second nerve cell, the
postganglionic neuron

6
The Autonomic Nervous System
• The autonomic nervous system
– Has an important function in maintaining the internal
environment of the human body in a steady state
» Role is vital in returning the body to a homeostatic state after
trauma
– Conveys sensory impulses to
» The blood vessels
» The heart and
» All of the organs in the chest, abdomen & pelvis

7
 The autonomic nervous system cont.
• Works generally without voluntary control (below the
conscious level)
– Autonomic = self governing
• We do not consciously direct
• Rate of the heart beat / heart rate
• Diameter of the blood vessels
• Blood pressure
• Digestion
• Respiration
• Blood pH
• The need to stimulate salivary glands to produce saliva etc
• It was believed that ANS was wholly independent of the CNS
– This is not quite the picture and there is some CNS component
involved

8
 The autonomic nervous system cont.
• Impulses often do not reach our consciousness but elicit
largely
• Automatic or reflex responses through the efferent autonomic nerves
– Thereby eliciting appropriate reactions of the heart, vascular system, etc
• E.g. when level of nutrients with in the blood stream falls
– Sensory nervous system picks this up &
• Stimulate the ANS to activate the food seeking behavior
• Also stimulates the digestive process
• However the effects of the ANS do impinge on our
consciousness
– Especially at times of heightened emotion, fear, sexual excitement
• We become aware of our hearts beating faster

9
 Autonomic Nervous System
• ANS is classified based on anatomic origin and neurotransmitter release
A. Based on the anatomic origin of out flow
– Divided in to two
• Sympathetic division
– Come from thoracic and lumbar regions of the spinal cord
– Preganglionic nerves are short & synapse in paired ganglia adjacent to spinal
cord
– Is the “Fight or Flight” branch of the ANS
» Increases Cardiac output and Pulmonary ventilation
» Directs blood to muscles
» Raises blood glucose
» Slows down digestion, kidney filtration & other functions not needed
during emergencies
» Whole sympathetic system tends to “go off” together
– Sympathetic system not required in controlled environment

10
11
 Autonomic Nervous System cont.
• Parasympathetic divisions
– Comes from cranial & sacral regions of the CNS
– Have long preganglionic nerves which synapse at ganglia near
or on the organ innervated
– Is the “Rest & Digest” branch of the ANS
» Promotes normal maintenance of the body
» Acquires building blocks and energy from food
» Involved in urination, defecation & getting rid of the wastes
» Promotes secretion & mobility of different parts of the
digestive tract
» Does not “go off” together; activities initiated when
appropriate
• Sympathetic & Parasympathetic systems often function
in antagonistic ways

12
13
Note that the nerve messages are not sent along continuous 'telephone lines'14
 B. Depending on neurotransmitter release
• In the ANS there are two nerves between the CNS and the
organ
– The nerve cell bodies for the second nerve are organized into ganglia
• CNS  Preganglionic nerve  Ganglion  Postganglionic nerve  Organ
– At each junction neurotransmitters are released to carry the signal to the next
nerve or organ

• Neurons in these systems classified

– Based on chemical neurotransmitters they release to mediate a nerve
impulse

Sympathetic
Parasympathetic
Pre
Pre Pst Thoracic Pst
ACH ACH ACH NE
Cranial Lumber
Sacral
Ganglion Ganglion

15
• Adrenergics
– Produce norepinephrine as principal neurotransmitter
• In postganglionic neurons of the sympathetic nervous system
• Cholinergics
– Produce acetylcholine as neurotransmitter in all
• Preganglionic fibers of the ANS (both sympathetic &
parasympathetic)
– Postganglionic fibers of the parasympathetic division and
in the exceptions of the sympathetic division
- Exceptions: sweat glands, piloerector muscles &
some blood vessels have sympathetic fibers
releasing ACH
OH
O
+ HO NH2

N(CH3)3Cl-

H3C O
HO
Norepinephrine
Acetylcholince chloride

16
 Cholinergic nervous system
• Innervates
– Both smooth & cardiac muscle
– As well as certain exocrine glands
• E.g. Salivary & sweat glands
• Are responsible for
– Stimulating contractions of smooth muscle in
• GIT
• Urinary tract
• Eye
• Decrease the heart rate
• Relax smooth muscle of blood vessel (vasodilation)

17
• Acetylcholine
– Function as a chemical messenger or neurotransmitter
– Released from the presynaptic nerve endings into the synapse
– It traverses the synaptic space and
– Interact with specific receptors at a postsynaptic site
• Interaction leads to a receptor mediated response
• Synaptic acetylcholine esterase catalyses hydrolysis of ACH
– To afford the inactive acetate and choline thereby regulating activity of
ACH

O
+ +
N (CH3)3 N(CH3)3
Acethylcholine
N+(CH3)3
Choline acetylase
HO esterase
Choline
+ ACCOA H3C O HO + CH3COOH
Choline

Biosynthesis Hydrolysis

18
 Receptors of ANS

• Basically classified into two

H

H
H N
N+(CH3)3Cl-

H3C CH3
Muscarine chloride N Nicotine

Muscarnic R
(M1-M5)
Cholinergic R
Nicotinic R
(NN & NM)
19
• Ach has two types of activities:
– Muscarinic
– Nicotinic
• Muscarinic activity
– Selective action of ACH similar to that of the alkaloid muscarine
• On the heart, glands & smooth muscle

• Nicotinic activity
– Activities resembling those of the alkaloid nicotine
• On autonomic ganglia and skeletal muscle

20
Muscarinic Receptor Activation

21
Muscarinic Receptor Activation

22
 Cholinergic Drugs
• Are drugs that mimic the effects of
acetylcholine
• Can be classified in to two groups
– Direct acting (Agonist)
• Drugs whose qualitative mode of action is the same as
that of ACH (Choline esters)
– indirect Acting cholinergic drugs
• Inhibit the hydrolysis of ACH by AChE
– Eg. Physiostigmine

23
 Directing acting Cholinergic Drugs
• ACH is an important neurotransmitter in the ANS
• An imbalance in the parasympathetic tone
– Leads to serious consequences & physiologic difficulties
• ACH deficiency can conceptually be treated by administering the
neurotransmitter itself
– But ACH is a poor therapeutic agent
• Non-selective in its action
– Produce effects at all cholinergic receptor sites
» Leading to undesired side effects
• Poorly absorbed across biological membrane
– B/s it is a quaternary ammonium salt
• Chemically liable due to rapid hydrolysis of the ester group in aqueous
media
– These forced medicinal chemists to think of an alternative

24
 Structural activity relationship
• Simple chemistry of ACH
• Ease of testing for ACH biological activity
– Allowed numerous chemical derivatives to be synthesized and studied
• To review SAR and examine effects of chemical modification
– Divide the structure into three components

Acyloxy Quaterinary
O
group ammonium
group
+ -
H3C O C C N (CH3)3 Cl
H2 H2

Ethylene
group

25
 Structural activity relationship cont.
• Modification of the quaternary ammonium group
– Analogues where
• Arsenic
• Phosphorous
• Sulfur
– Replaced nitrogen were synthesized
– Although they exhibited some ACH activity
• They were less active & not used clinically
• The onium group
– Is essential for intrinsic activity and contributes to the affinity of the
molecule for the receptors partially through
• Binding energy
• Its action as a detecting & directing group
– Molecular modeling data showed the binding site to be
• A negatively charged aspartic acid residue
– In the third position of the seven trans membrane helixes of the muscarinic
receptor

26
 ACH receptor

Hydrophobic pockets

O
C
O
Asp C
O
H-B
O
N

27
 Structural activity relationship cont.
It is concluded that
• Only compounds possessing a positive charge on the atom in
the position of the nitrogen had appreciable muscarinic
activity
• Replacing all the three methyl groups on the nitrogen by
larger alkyl groups leads to loss of agonist activity
• When the three methyl groups are replaced by ethyl groups
– The resulting compound is a cholinergic antagonist
• Replacement of only one methyl group by ethyl or propyl
group
– Affords an active compound
• But much less active than ACH
• Successive replacement of one, two or three methyl groups
with hydrogen atoms
– Affords a tertiary, secondary or primary amine
• Leading to successively diminishing muscarinic activity

28
 Modification of the ethylene group
• There should be no more than five atoms
– Between the nitrogen & the terminal hydrogen atom for maximal
activity
• Replacement of hydrogen atoms of the ethylene bridge
– By alkyl groups larger than methyl
• Affords compounds much less active than ACH
• Introduction of a methyl group on the carbon  to the 40 nitrogen
– Affords acetyl- -methylcholine (methacholine)
• Is selective for muscarinic receptors
• Has muscarinic potency equivalent to that of ACH
• Possesses much greater muscarinic potency than nicotinic potency
• A methyl group on the carbon -to the 40 nitrogen
– Affords acetyl -methylcholine
• Relative to ACH, activity is reduced at both muscarinic & nicotinic
receptors
– It exhibits greater nicotinic than muscarinic potency

29
 Modification of the ethylene group cont.

hinder binding to esterase & provide a sheild

O CH3 to nucleophilic attack
O
N(CH3)3
H3C O
N(CH3)3
Acetyl-b-methylcholine H3C O

CH3
acetyl-a-methylcholine

30
 Modification of the ethylene group cont.
• Distance from the nitrogen to the ester group is
important
– The ethylene bridge between the ester and the
nitrogen atom can not be extended
• Addition of methyl groups to either one or both the
ethylene carbons
– Results in asymmetric molecules
• Exhibiting optical isomerism
• Muscarinic receptors & AChE
– Display stereo selectivity for the enantiomers of
acetyl- -methylcholine
• The S(+)-enantiomer is equipotent to ACH
• The R(-)-enantiomer is about 20X less potent as ACH

31
 Modification of the acyloxy group
• The ester functional group is essential
• Replacing the acetyl group by higher homologue (propionyl
or butyryl)
– The resulting ester is less potent than ACH
• Choline esters of
– Aromatic or high mol. wt. acids
• Possess cholinergic antagonist activity
• Chemical instability of ACH can be solved by
– Replacing the acetyloxy group with a functional group resistant to
hydrolysis
– Lead to the synthesis of carbamic acid ester of choline
• A potent cholinergic agonist - Carbachol
– Possessing both muscarinic & nicotinic activity
– Less readily hydrolyzed in the GIT or by AChE
» Can be administered orally

32
 Modification of the acyloxy group cont.

O O CH3

N(CH3)3 Cl N(CH3)3 Cl
H2N O H2N O

Carbachol Bethanechol

33
Acetylcholine esterase inhibitors (AChEI’s):
Indirect acting cholinergic agents
• In the Cholinergic nervous system action of ACH is
terminated by
– Its rapid AChE catalyzed hydrolysis
• To acetic acid and choline

• Inhibition of AChE
– Increases concentration of ACH in the synapse
• Results in production of both muscarinic & nicotinic responses

34
Acetylcholine esterase inhibitors cont.

N(CH3)3
H3C O

H2O, AChE

O CH3

H3C OH
+ HO
N(CH3)3

35
 Therapeutic applications of AChE’s
• AChE inhibitors also called anticholinesterases
– Are classified as indirect cholinomimetics
• B/s principal mechanism does not involve binding to
cholinergic receptors
• Used therapeutically
– To improve muscle strength in myasthenia gravis
– To treat glaucoma
– To treat symptoms of Alzheimer's disease & similar
cognitive disorders
– Other conditions characterized by cholinergic deficiency in
the cortex & basal forebrain
– Also used as insecticides & in chemical warfare

36
 Reversible inhibitors of AChE
• Are substrates for & react with AChE
– To form an acylated enzyme which is more stable than the acetylated enzyme
• But still capable of undergoing hydrolytic regeneration
• Clinically useful inhibitors are those of the first type & include
– Aryl carbamates
• Esters of carbamic acid & phenols such as physiostigmine
– Alkyl carbamates
• Esters of carbamic acid and alcohols such as carbachol and bethanechol
• Aryl carbamates & Alkyl carbamates are structurally related to ACH
– Are substrates for AChE
– Competitively inhibit AChE
– Are hydrolyzed very slowly by AChE

37
Structure of AChE inhibitors
O

Me O
Me
O
N
N(CH3)3
H2N O
H

N N
Carbachol
Urethane Me Me
or
Carbamate
Physiostigmine

O CH3

N(CH3)3
H2N O

Bethanechol

38
Mechanistic steps in hydrolysis of Ach

O
OH
AChE-Se-OH +
N(CH3)3
N(CH3)3
H3C H3C O
O
A O-Ser-AChE
B

O
O

H2O +
N(CH3)3
H3C OH HO
H3C O-Ser-AChE

+ C (inactive)

AChE-Ser-OH

39
 Aryl carbamate AChE inhibitors
• When aryl carbamate AChE inhibitors
– Such as physiostigmine and its analogues bind to
the catalytic site of AChE
• Hydrolysis of carbamate occurs
– Which trans esterifies the serine residue with carbamic acid
» To give the carbamylated enzyme

• Rate of carbamylation is in the order of

– Carbamic acid esters>methylcarbamic acid esters>dimethylcarbamic acid esters

H2N O-Ser-AchE Carbamylated AchE

40
 Aryl carbamate AChE inhibitors cont.
• Regeneration of active AChE by hydrolysis of
the carbamylated AChE
– Much slower than hydrolysis of the acetylated
enzyme
O

O
H2O
H2N O-Ser-AchE
+ AchE-Ser-OH
Carbamylated AchE H2N OH

CO2 + HNR2

41
 Analogues of Physiostigmine
• Physiostigmine has limited medicinal use since it has serious side-
effects
• as a result it has only been used in the treatment of glaucoma
• Simpler analogues have been made
Me
Me
CH
N O
H NMe2

• Miotine still has the necessary carbamate, aromatic, and tertiary

aliphatic nitrogen groups.
• It is active as an antagonist but suffers from the following
disadvantages:
It is susceptible to chemical hydrolysis.
It can cross the blood-brain barrier.
– This results in side-effects due to its action in the CNS 42
• Neostigmine was designed to deal with both the problems
described above.
• a quaternary nitrogen atom is present
• Since the molecule is permanently charged, it cannot cross
the blood-brain barrier and cause CNS side-effects.
– Increased stability to hydrolysis is achieved by using a
dimethylcarbamate group rather than a methylcarbamate group

Me

N O NMe3
Me

43
 Pyridostigmine
• Incorporates charged nitrogen into a pyridine ring
• has longer duration of action & a lower incidence of toxicity
than neostigmine
• Better choice for oral therapy of myasthenia gravis

Me
CH3
N O
Me N

44
• Three AChEI’s have been approved for treatment of Alzheimer disease: Rivastigmine,
tacrine and donepezil
Rivastigmine
• Because of slow dissociation of the carbamylated enzyme, it has been referred as a
pseudo-irreversible inhibitor
CH3
CH3

Me
O N CH3
N

Me
O

Tacrine & donepezil

• Lacks carbamate moiety & classified as nonclassical AChEI’s
• Tacrine has limited use because of hepatotoxicity
• Compared to tacrine, donepezil exhibit greater CNS selectivity, longer
elimination half life & little or no potential for hepatotoxicity
NH2 H3CO
H2
CH2 N C

H3CO
N Donepezil
Tacrine
45
 Irreversible inhibitors of AChE
• Are substrates for AChE
– Result in an acylated enzyme
• More stable to hydrolysis than a carboxylate
• Phosphate esters are very stable to hydrolysis
– Are more stable than many amides
• Act as inhibitors by the same mechanism as the
carbamate inhibitors
– Except that they leave the enzyme esterified as phosphate
ester

46
• Therapeutically important ones
– Diisopropylflurophosate & Echothiophate iodide
(phospholine)
• Because of their toxicity, not used for their systemic
action
– Have topical therapeutic application for the treatment of
glaucoma
» Decrease in intraocular pressure they cause can last up to 4 weeks

O O N+(CH3)3I-
H3C CH3

O P O H3CH2CO P S

H3C CH3
F OCH2CH3

Diisopropylfluorophosphate (DFP) Echothiophate iodide

47
• Many lipophilic derivatives of phosphoester AChEIs
designed as insecticides
– are beneficial in agriculture worldwide

O
S S O
H3CO P S OCH2CH3
H3CH2CO P O NO2 H3CH2CO P O NO2
OCH3 OCH2CH3 OCH2CH3 OCH2CH3

Malathion O Parathion Paraoxon

Cl O O
S O
H3C
H3CH2CO P O Cl (H3C)2N P O P N(CH3)2 O P F
OCH2CH3 H3C CH3
Dichlorfenthion
N(CH3)2 N(CH3)2 Sarin
Schradan

48
• These insecticidal compounds:
– are extremely lipophilic
– have high vapor pressure
• Hence should be used with caution to avoid
– Absorption through the skin
– Inhalation of the vapor
» Number of fatal poisonings reported every year
– Those having a sulfur atom on phosphorous with coordinate covalent
bond
• As such exhibit little AChEI activity
• But are rapidly bioactivated by microsomal oxidation in insects
– To afford the corresponding oxo derivatives (phosphate esters) which are very
potent

S O
H3CH2CO P O NO2 Bioactivation H3CH2CO P O NO2
OCH2CH3 OCH2CH3

Parathion Paraoxon

49
 Antidote for irreversible AChEIs
• Hydroxyl amine (NH2OH) is a strong nucleophilic compound
– Can efficiently cleave phosphate esters
– Significantly increase rate of hydrolysis of phosphorylated AChE
• But at concentration that is toxic
• Would be logical to design a compound with
– High degree of selectivity to AChE
– Strong binding affinity for AChE
– Carry a hydroxyl amine like nucleophyle into close proximity to the phosphorylated serine residue
• 2-pyridine aldoxime methyl chloride (pralidoxime) is the only drug with
such activity

N
HO
N Cl
H
CH3

Pralidoxime chloride (2-PAM)

50
 Reactivation of AChE with 2-PAM
O
(2-pyridine aldoxime methyl)
N
+ OH
AchE-Ser-O-P-(OR)2
N

H O
CH3

AchE-Ser O P (OR)2

H O N
N
O
H CH3
PAM O P (OR)2 + AchE-Ser.OH
H

51
• Important feature of irreversible phosphodiester
derived AChEIs
– Can undergo a process known as aging
• Aging plays an important role in the toxicity of these
irreversible AChEIs

O O O

Aging Aging
AchE-Ser-O P OR AchE-Ser-O P O AchE-Ser-O P O

OR OR O

52
 Anticholinergics
Muscarinic antagonists
• Commonly referred to as
– Anticholinergics, antimuscarinics, cholinergic blockers, antispasmodics,
parasympatholytics
• Have high binding affinity for muscarinic receptors
– But no intrinsic activity
• Antagonists bind to receptors to produce no response
• Act as competitive antagonists of ACH
– Having pharmacologic effects opposite that of muscarinic agonists
• Responses of muscarinic antagonists include
– Decreased contraction of smooth muscle of GIT & urinary tract
– Dilation of the pupils
– Reduction of gastric secretion
– Decreased secretion of saliva

53
Muscarinic antagonists
• Have therapeutic value in treating
– Smooth muscle spasm
– Gastric ulcer
– In ophthalmic examinations
– Shutting down digestion for surgery
– Treatment of Parkinson’s Disease
– Anticholinesterase poisoning
– Motion sickness
– Compounds possessing muscarinic antagonist activity are
common components of cold and flu remedies
• To reduce nasal & upper respiratory tract secretions

54
• Atropine is the tropic acid ester of tropine
– The naturally occurring alkaloid is (-)-hyoscyamine
– Source - roots of Atropa belladonna

Me
N
easily racemised
H
CH2OH

O CH
C *

O
• Used as a poison
• Used as a medicine
- decreases GIT motility
- antidote for anticholinesterase
poisoning
- dilation of eye pupils
- CNS side effects – hallucinations

55
• Scopolamine - is the generic name given to (-)-hyoscine, the
naturally occurring alkaloid obtained from thorn apple.
Me
N

H
O CH2OH

H O CH
C *
H
O
Medical use –
• treatment of motion sickness
• Used as a truth drug (CNS effects)

56
• Atropine is the prototype anticholinergic agent
– It provided the structural model that guided the design and synthesis
– Circled portion depicts segment resembling ACH
• In atropine
– Amine group separated from the ester by more than two carbons
• But conformation assumed by tropanol ring orients these two
atoms at a distance similar to that of ACH

O
H
N-CH3 O C C

H2C

OH

57
 Comparison of atropine with acetylcholine

Me
N

H
CH2OH

O CH
C
O

• 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
 Structural analogues based on atropine
• Both atropine and hyoscine are tertiary amines rather than
quaternary salts
– Thus are able to cross the blood brain barrier
• Antagonize muscarinic receptors in the brain leading to CNS effects like
– Hallucinogenic effects at high dose
– Restlessness
– Agitation
– Hyperactivity
• Disorienting effects of scopolamine made it useful as
– Truth drug for the interrogation of spies
• To reduce CNS side effects
– Quaternary salts of atropine are often used clinically
• Ipratropium as a bronchodilator
• Atropine methonitrate to lower motility of the GIT

59
 CH(CH3)2 CH3

Br NO3
N N
H3C H3C

H H
CH2OH CH2OH

O CH O CH
* *

O O

Ipratropium Atropine methonitrate

60
• Solanaceous alkaloids
– are potent cholinergic blockers
• But produce wide range of undesired effects
– through their nonspecific blockade of autonomic functions
• Efforts to use antispasmodic effects of atropine often results in
- dryness of the mouth
- fluctuations in pulse rate
• SAR studies are carried out so as to get a better congener
• Important groups while synthesizing analogues of atropine are:
– the basic nitrogen
• An important binding group and interacts in the ionic form
– the aromatic ring
– the ester group
– Complex ring system of atropine may not be necessary for antagonistic activity

61
• The general structure atropine derivatives is indicated as follow:

• Synthesis of cpds with similar action but decreased side effects

were lead to new anticholinergic drugs which delinate with a
chemical structure:
• Aminoalcohols
• Aminoalcohol esters
• Aminoalcohol ethers
• Aminoamides

62
• Aminoalcohols
– are similar to the classic anticholinergic cpds derived from
atropine
• Have antiparkinsonian property
– Need to have a tertiary nitrogen to pass BBB
– Quaternization of these amino alcohols has been utilized
to enhance
• Antispasmodic & antisecretory activities

CH2CH2 C2H5
N
C CH2CH2 N C2H5 Cl
OH
C2H5
H2C
OH

Tridihexethyl chloride
Biperiden
antispasmodic & antisecretory
Useful in Parkinson's syndrome

63
• Aminoamides
– Represent the same type of molecule as the amino alcohols
• With the important exception that the polar amide group
– Replaces the corresponding polar hydroxyl group
– Isopropamide iodide is the only drug of this class currently in use
• Produces atropine like effects
– Provide antispasmodic and antisecretory effects for as long as 12hrs

C2H5
I
CH2CH2 N C2H5

C2H5
C NH2

Isopropamide iodide

64
 Aminoalcohol esters
• Are primarily used as antispasmodic or mydriatics
• Clindinum is marketed alone & in combination with chlordiazepoxide
(anxiety reducing agent)
• The rationale of the combination for the treatment of GIT complaints is
based on the recognition of anxiety to the development of the disease
condition
• Glycopyrrolate is more potent on M1 than on M2 & M3
• The low affinity of M2, inpart, explain the low incidence of toxicity
associated with this drug

O
O

C O Br
C O
C
C
OH N OH
CH3
N
H3C CH3
Clindinium glycopyrrolate
65
Eucatropine Hydrochloride
Used as Mydriatic agent Mepenzolate Bromide
Relieve pain, cramp and bloating and curb diarrhea

Cyclopentolate
Oxyphencyclimine Hydrochloride Ophthalmic examination
Anticholinergic and antisecretory

66
 Aminoalcohol ether
• Closely related to antihistamine
• do possess antihistaminic properties

CH3
O CH2CH2 N
C CH3
H

CH3
Orphenadine
antiparkinsonian

67
 Nicotinic receptors
• Are coupled directly to ion channels
– Mediate very rapid responses when activated by ACH
• Ion channels are responsible for
– Electric excitability of nerve cells
– Sensitivity of sensory cells
• Nicotinic receptors subtypes
– Nicotinic receptors at the neuromuscular junction [in sympathetic
nerves terminating directly at skeletal muscle (no synapse) ]
• Termed as N1 nicotinic receptors
– Blocked by succinylcholine, d-tubocurarine & decamethonium
– Stimulated by phenyl tetramethonium
– Nicotinic receptors found in the autonomic ganglia
• Termed as N2 nicotinic receptors
– Blocked by hexamethonium
– Stimulated by tetramethylammonium, dimethyl-4-phenylpiperazinium
(DMPP)
– Nicotinic receptors also identified in many regions of the CNS
• But their pharmacologic function is not yet understood fully

68
 Nicotinic antagonists
• Nicotinic receptors present in
– Nerve synapses at ganglia
– The neuromuscular synapse
• Drugs are able to show selectivity between the two sites
– Because of the distinctive routes which have to be taken to
reach them
• Antagonists of the ganglionic nicotinic receptor sites are not
useful therapeutically
– Can’t distinguish between ganglia of
• Sympathetic and parasympathetic nervous system
– Consequently have many side effects
• Neuromuscular blockers are therapeutically useful
– Nicotinic antagonists
• Chemical compounds that bind to nicotinic receptors but with no
efficacy

69
• Therapeutically useful neuromuscular blockers are classified as
non depolarizing and depolarizing neuromuscular blockers.
• Non depolarizing neuromuscular blockers are competitive nicotinic
antagonists
» i.e. effects are reversible with ACH
• Tubocurarine is the first known neuromuscular blocking agent
– Is important to the understanding of nicotinic antagonists as atropine was to
muscarinic antagonists
• Therapeutically useful compounds in this group also referred to as
drugs with
– Curariform
– Curarimimetic activity
– Pachycurares

• Depolarizing agents – cause depolarization prior to relaxation

70
 Nondepolarizing blocking agents
• drugs that compete with ACH for the recognition site on the
nicotinic receptor
• Thus, decrease the effective ACH-receptors combination
– The end plate potential becomes too small
» To initiate the propagated action potential

• Tubocurarine chloride is a prototype competitive antagonist of

nicotinic neuromuscular acetylcholine receptors, It is one of the
chemicals that can be obtained from curare, itself an extract of
Chondodendron tomentosum, a plant found in South American
jungles which is used as a source of arrow poison.

• Native indians hunting animals with this poison were able to eat
the animal's contaminated flesh without being affected by the
toxin because tubocurarine cannot easily cross mucous
membranes and is thus inactive orally

71
• Tubocurarine began to be
clinically utilized as a surgical
neuromuscular blocking agent in
the 1940’s

• This drug has been supplanted

by safer medicines, but is still
utilized as part of the lethal
injection procedure.
• Compounds in this class can have one or two 40 ammonium
groups
– However, those with only one 40 ammonium group
• Exist as bis-cations in vivo
– Due to having the second positive charge on a protonated tertiary
amine
• Structure of this compound serves as a scaffold
– To position the two positive charges in the correct three dimensional
orientation
• For interaction with trans membrane nicotinic receptors

73
• Reaction of d-tubocurarine with CH3I affords metocurine
iodide
– In which the two phenolic OH groups of tubocurarine are changed to methyl
ether
– The tertiary amine becomes quaternary
• Metocurine is about X4 more active than tubocurarine in neuromuscular blocking
activity
I
H3C R RO OCH3

H3CO O H3C
CH3

RO d-tubocurarine iodide (R=H)

Metocurine iodide (R=CH3)

74
Pharmacophore
• Two quaternary centres at specific separation (1.15nm)
• Different mechanism of action from atropine based antagonists
• Different binding interactions

Clinical uses
• Neuromuscular blocker for surgical operations
• Permits lower and safer levels of general anaesthetic
• Control ventilation i.e. facilitation of endotracheal intubation
• Prevention of trauma in electro shock therapy of psychiatric disorder
• E.g. Succinyl choline
• Relocate dislocated joints and fractured bones
• Tubocurarine used as neuromuscular blocker but side effects
Steroid based neuromuscular blocking agents
O

O C CH3
CH3

R2

CH3 H
R1

H H

R3O O
H H3C

Pancuronium R1 = R2 = N
R3 = CH3

O
H3C

Vecuronium R1 = R2 = N R3 =
N CH3

CH3 O
Pipecuronium R1 = R2 = N N R3 =
CH3
CH3

N
Rocuronium R1 = N O R2 = H
R3 =

76
 O

O Me
Me

Me H N
N
Me
H H

O
H

O Me

• Steroid acts as a spacer for the quaternary centres (1.09nm)

• Acyl groups are added to introduce the Ach skeleton
• Faster onset then tubocurarine but slower than suxamethonium
• Longer duration of action than suxamethonium (45 min)
• No effect on blood pressure and fewer side effects
 Pancuronium bromide

 Synthetic bisquaternary agent.

 It is five times as potent as d-tubocurarine. Unlike d-tubocurarine, it

does not cause release of histamine or block of ganglionic
transmission.
 Like d-tubocurarine, it has a moderately long onset (2.9 min) and
duration of action (110 min).
 Vecuronium bromide
 Structurally Similar to pancuronium except for a tertiary
amine in place of a quaternary nitrogen.

 Vecuronium has a moderate onset of action (2.4 min) and a

duration of action of about 50 min.
 Rocuronium bromide
 has a rapid onset of action (1 minute), and intermediate
duration of action (55 minutes)

 On rare occasions, it may release histamine and cause

cardiac irregularities.
 Rapacuronium bromide
 Is an analogue of vecuronium.
 It has a rapid onset of action (1.5 minutes) and a
short to intermediate duration of action (20 min).
 Suitable alternative to mivacurium or succinylcholine
for short procedures.
 Tetrahydroisoquinine based neuromuscular
blocking agents
13.3 Analogues of tubocurarine

MeO OMe
O O
Me H
N C C N
MeO CH2 CH2 O (CH2)5 O CH2 CH2 OMe

Atracurium OMe MeO

OMe OMe

sign based on tubocurarine and suxamethonium

cks cardiac side effects
pidly broken down in blood both chemically and metaboli
oids patient variation in metabolic enzymes
fetime is 30 minutes
ministered as an i.v. drip
lf destruct system limits lifetime
 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine

Me Me
N
R -H R
N
CH2 CH C H2C CH C
O O
H
Ph Ph
ACTIVE INACTIVE

Atracurium stable at acid pH

Hofmann elimination at blood pH (7.4)
• An improved version of atracurium is the purified form of just
one of the ten possible stereoisomers, that has the highest efficacy
and least side effects
• The name of the blocking agent is cisatracurium (NIMBEX)
• This is the most widely used agent surgically.
• 80% of the drug is metabolized via Hofmann elimination, thus
lowering
variability in patients with possible liver or renal disease.
• The Hofmann degradation is only dependent on the pH and
temperature of the
plasma.
 Depolarizing blocking agents
• Drugs in this category are known to bring about
– Depolarization of the membrane of the muscle end plate
• This depolarization is similar to that produced by ACH
– At ganglia & neuromuscular junction

» So known as nicotinic effect

• Smooth or voluntary muscle when challenged repeatedly with a

depolarizing agent eventually become insensitive
– A phenomenon known as Tachyphylaxis or Desensitization making
the plates insensitive to ACH in a few minutes.

85
• Succinylcholine (suxamethonium chloride)
– Represents two molecules of acetylcholine
• Connected at the carbons  to the carbonyl of the acetic acid
moiety
– Is rapidly hydrolyzed & rendered inactive both in plasma
and aqueous solutions by esterases
• This chemical property makes it of brief duration of action
– Thus used for rapid & short duration of neuromuscular blockage
O

O N(CH2)3 Cl

O
N(CH3)3 Cl

O
 Does not cross the BBB and placental barrier.
 It causes release of histamine from mast cells.
86
• Decamethonium bromide
(CH3)3N+ (CH2)10 N+(CH3)3
Br- Br-
• has long lasting, long recovery times, side eff
on heart
and thereby no longer use in clinical practi
• SAR study on a series of bis-quaternary ammonium compounds
– With varying number of methylene groups separating the nitrogen atoms
was done.
 Maximal neuromuscular blockage was observed with 10 to
12 unsubstituted methylene groups
 Activity diminishes as number of methylene groups increases
or decreases from the optimum number
Ex:(hexamethonium) is a Compound with six methylene
Groups nicotinic antagonist at autonomic ganglia 
Ganglionic blocking agent

87
 Ganglionic blockers
• To conduct nerve impulses
– The cell must be able to carry out
• A polarization & depolarization processes
– If the depolarized condition is maintained without repolarization
» It is obvious that no conduction occurs

Depolarizing ganglion blockers

– These blocking agents are actually ganglionic stimulants
– Small doses of nicotine give an action similar to that of ACH
• An action known as nicotinic effect of ACH

88
 – Larger amount of nicotine bring about ganglioinc block
Characterized initially by depolarization
Followed by a typical competitive antagonism
– This depolarization of the membrane of the muscle end plate
is quite similar to that produced by ACH in high concentration
– Chemicals that cause this type of ganglionic block
– Are not of therapeutic significance
• Outcome of ganglionic block on different organs
– Heart  on parasympathetic system  tachycardia
– Veins  on sympathetic system  dilation
– Urinary bladder  parasympathetic  urinary retention
– Sweat glands  sympathetic  anhidrosis

89
Non depolarizing competitive ganglionic blockers
• Compounds in this class Possess the necessary affinity to attach to the nicotinic
receptor sites specific to ACH
• But lack the intrinsic activity necessary for impulse transmission
– Because they are unable to effect depolarization of the cell

• In the presence of a fixed concentration of the blocking agent

– A large enough concentration of ACH can offset the blocking action
• By competing successfully for the specific receptors
– Either the agonist or the antagonist can displace the other
» If present in higher concentration

N
N
N

Tetraethylammonium (40 nitrogen) Hexamethonium (bis 40 nitrogen)

90
• Non depolarizing non competitive ganglionic blocking agents:
– These blocking agents exert their effect not at specific ACH receptor site
• But at some point further along the chain of events necessary for the transmission
of the nerve impulse
– With the block imposed, increasing concentration of ACH has no effect
• Apparently ACH does not act competitively with the blocking agent at the same
receptors
– Examples in this class are trimethaphan camsulate & mecamylamine
hydrochloride
• However, mecamylamine hydrochloride possesses both competitive and
noncompetitive components
– So called a dual agonist

NHCH3
C N N C
H2 H2 CH3
HC CH CH2
CH3
H2C CH CH2
S CH3

H2C C Mecamylamine Hydrochloride

H2
20 nitrogen
Trimethaphan Camsulate 91
0
3 nitrogens
 Adrenergic drugs
• The terms adrenergic nervous system and sympathetic nervous system are
used interchangeably
• Act on effecter cells through
– Adrenoceptors that are normally activated by the neurotransmitter
• Norepinephrine (noradrenaline) [NE]
» Or
– They may act on neurons which release the neurotransmitter
• Norepinephrine & epinephrine
– Are members of a class of pharmacologically active substances known as
catecholamines
• Because they contain with in their structure
– Both an amine and ortho dihydroxy benzene (catechol)

HO RHN

R = H; Norepinephrin
R = CH3; Epinephrin
HO

OH

92
 Biosynthesis, storage & release of NE
• Biosynthesis of NE takes
HO COOH

L - Tyrosine

place with in
NH2

– Adrenergic neurons near Tyrosin hydroxylase

the terminus of the axon HO COOH

L - dihydroxyphenylalanine
close to the junction HO
NH2

with the effecter cell Aromatic L - Aminoacid

decarboxylase

• Biosynthesis begins HO m
o

with the active HO

p
NH2 Dopamine

transport of L-tyrosine Dopamine hydroxylase

With in the storage
vesicle

into adrenergic cell

OH

HO NH2

Norepinephrine
HO

93
 Reuptake & metabolism of NE following release
Following its release
• NE diffuses through the intracellular space
– To bind reversibly to adrenoceptors (,)
• On the effecter cells triggering a biochemical cascade
– Resulting in physiologic response
– In addition to the receptors on effecter cells
• There are also adrenoceptors responding to NE (2-receptors) on the presynaptic
neurons
– Which on stimulation, act to inhibit release of additional NE in the synapse
• Once NE is released and cause stimulation at various receptors
– There must be a way of removing it from the synapse
– To terminate the adrenergic impulse
• Recycling through active transport uptake into presynaptic neuron (uptake-1) up to
95% of NE go into recycling as such
• Less efficient processes (Uptake-2) operates only at high con. of NE
– Portion of NE which escapes uptake-1 diffuses out of the synapse &
» Gets metabolized in extraneuronal sites by catechol-O-methyl transferase (COMT)
where the meta OH is methoxylated
- Which methylates the meta hydroxyl group
• NE is also metabolized by MAO to 3,4-dihydroxyphenylglycoaldehyde (DOPGAL)

94
 Adrenergic receptors
• Adrenergic receptors were classified as  & 
– Based on their responses to different adrenergic agonists
• Norepinephrine
• Epinephrine
• Isoproterenol
• Those designated as  are stimulated by these agonists
– Epinephrine (?) > norepinephrine (?) > isoproterenol
• Those designated as  get stimulated in the order
– Isoproterenol > epinephrine > norepinephrine
• Additional agonists and antagonists were used
– In further subtype classification as
• 1 & 2
• 1 & 2
– Molecular cloning helped in characterizing 3

95
 Therapeutic relevance of adrenergic receptors
Organ responding Major receptor type Response

Ateriols 1 Constriction
2 Dilation
Vascular smooth muscle 2 Dilation

Eye (radial muscle) 1 Contraction (papillary

dilation)
Fat cells , lipolysis

Heart 1 Increase rate & force

Increased conduction velocity

Intestine ,  Decreased motility

Liver , 2 Increased gluconeogenesis

and glycogenolysis

Lungs 2 Relaxation (bronchial dilation)

Uterus 1 Contraction (In pregnant women)

2 Relaxation
96
 Norepinephrine & adrenergic drugs
• NE has limited clinical application
– It is nonselective
– Given only intravenously
• Due to metabolism by intestinal & liver COMT & MAO
– Low lipophilicity
– Rapid metabolism limits its duration of action
• Only 1-2min given by infusion
• NE administered
– To counteract hypotensive crises and cardiac arrest
• Epinephrine is more widely used clinically than NE
– Although it lacks oral activity for the same reason as NE it is used to
• Treat hypotensive crisis
• Stimulate the heart in cardiac arrest (due to its greater -activity)
• Given i.v. to inhibit uterine contraction
• In form of inhalation to relieve bronchoconstriction in asthma

97
 SAR of adrenergic agonists
• Agents in this class
Phenylethanolamine agonists
• B/s of the basic amino group
– Have an OH on C-1 of
the side chain, -to the
– pKa range b/n 8.5-10 amine
– All these agents are • The OH substituent must
highly positively be in the R absolute
configuration
charged at – For maximal activity
physiologic
1' pH OH
– Although most are
6'
2' 1
NH R1
available as + on market
2
R3 • Nature of the other substituents
3' 5' R2
determine
4'
– Receptor selectivity
Phenyl ethanolamine agonists
– Duration of action
98
 R1 substituent on the amino nitrogen
• Increase in size from OH
2'
– Hydrogen  methyl  isopropyl 3'
1'
1
NH R1

– Norepinephrine  epinephrine  isoproterenol R3

2

• Activity at -receptor decreases (?) and 4' 6' R2

• Activity at -receptors increases 5'

• Activity at  & -receptors is maximal when R1 is methyl as in epinephrine

• -agonist activity is dramatically decreased when R1 is larger than methyl
– Is negligible when R1 is isopropyl as in isoproterenol leaving only -activity
• The -receptors have a large lipophilic-binding pocket adjacent to the amine binding aspartic
acid residue
– Which is absent in the -receptor
• As R1 becomes larger than butyl
– Affinity for 1-receptor returns but not intrinsic activity
• Which means large lipophylic groups can afford compounds with 1-blocking activity e.g.
Labetolol
• N- substituent can also provide selectivity for -receptors
– E.g. T-butyl group (Colterol)  selective for 2-receptors (agonist)
– Isoproterenol is a nonselective -agonist
• When considering use as a bronchodilator
– Nonselective -agonists such as isoproterenol has undesirable cardiac stimulatory effects

99
R1 substituent on the amino nitrogen cont.
OH
OH H
HO N
HO NH2

HO
HO
Isoproterenol
Norepinephrine A non selective-agonist

OH
OH H
HO N
H
HO N CH3

HO
HO Colterol
Epinephrine A selective 2 agonist

100
 R2 substituent -to basic nitrogen (carbon-2)
• Substitution of CH3 or C2H5 group at this
position
– Slow metabolism by MAO
• But has little effect on duration of action
• As the compound remains substrate for COMT
• An ethyl group in this position
– Diminishes -activity more than -activity
– Affords compounds with -selectivity
• E.g. ethyl norepinephrine OH

OH HO NH2
1'
6' NH R1
2' 1
2
R3 HO
3' 5' R2 101
Ethylnorepinephrine
 R3 substitution on the aromatic ring
• The natural 3’,4’-dihydroxy substituted benzene ring in norepinephrine
– Provides excellent receptor activity for both  & -sites
• Such catechol containing compounds have poor oral activity because
– They are hydrophilic & rapidly get metabolized by COMT
• Alternative substitution have been found
– That retain good activity &
– Render resistance to COMT metabolism
• 3’,5’-dihydroxy compounds (such as Metoproterinol)
– Are not good substrates for COMT
– Show selectivity for 2-receptors
• Metoproterinol is an orally active bronchodilator having little of the cardiac stimulatory properties of isoproterenol
• 3’-hydroxymethyl, 4’hydroxy substitution (pattern of albuterol)
– Enhances oral activity
– Produce 2 selectivity
– Impart resistance to COMT
• Compound with only 3’ hydroxyl group
– Activity reduced at -sites
– Activity almost eliminated at -sites OH
• Thus selective -agonists such as phenylephrine & metaraminol 2'
• Used as a nasal decongestant and as a mydriatic 1' NH R1
3' 1
2
R3
4' 6' R2

5'

102
R3 substitution on the aromatic ring cont.
OH

H OH
HO N
H
HO N CH3

phenylephrine
OH metoproterinol
OH OH CH3

H
HO NH2 N CH3

CH3
CH3 HO

albuterol
metaraminol
OH
OCH3 OH

NH2

CH3

Terbutaline
Methoxamine
OCH3 103
 R3 substitution on the aromatic ring cont.
• 2’,5’-dimethoxy substitution of methoxamine
» Selectivity for -agonists & -blocking activity at high
concentration
• When the phenyl ring has no phenolic substituent (R3=H)
– These phenylethanolamines may have both direct & indirect activity
• Direct agonist activity
– Due to stimulation of adrenoreceptors by the drug it self
• Indirect agonist activity
– Is the result of the displacement of norepinephrine from its storage
granules or reuptake inhibition resulting in non-selective stimulation
of the adrenoreceptors by the displaced norepinephrine
• Since norepinephrine stimulates both  & 1 receptors, indirect activity
can not be selective

104
 -Adrenergic agonists
• Examples of 1 agonists are:
– Phenyl ethanol amines such as
• Meteraminol
• Methoxamine
• Phenylephrine

– 2-aryl imidazolins such as

• Oxymethazolin
• Xylomethazoline
• Examples of 2 agonists are:
– 2-amino imidazolins such as
• Clonidine
105
 1-Adrenergic agonists

Phenyl ethanol amines

• Meteraminol & methoxamine are
– Selective to 1-receptors & have little cardiac stimulatory
properties, used in spinal anesthesia

– Not substrates for COMT & their duration of action is

significantly longer than norepinephrine
OH
OH
H3CO NH2
HO NH2

CH3
CH3
OCH3

Metaraminol Methoxamine 106

 1-Adrenergic agonists cont.
2-aryl imidazolins
• Contain a one carbon bridge b/n C2 of imidazol ring & a phenyl substituent
– Therefore the general skeleton of ethanolamine is contained with in the structure
• Are selective 1 agonists with vasoconstrictor and vasopressor activity
• Lipophylic substitution on the phenyl ring
– Ortho to the methyl bridge appears to be required for agonist activity at 1 & 2
receptors
– At meta or para positions provide selectivity for 1 receptor diminishing affinity for 2
receptors

CH3 CH3
H H
N HO N

H3C H3C
N N
CH3 CH3
H3C H3C
CH3 CH3
Xylometazoline Oxyometazoline

• Used as nasal and ophthalmic decongestant

107
 2 adrenergic agonists
Clonidine ( ά1: ά2, 300:1)
• Similar to imidazoline  1-agonists, clonidine has lipophilic ortho substituent
on the phenyl group
• O-chlorine group affords better activity than o-methyl group at  2 sites
• the most readily difference between clonidine & 1 agonists is the
replacement of CH2 bridge on C-1 of imidazoline by an amine NH
• The basicity of the guanidine group (typically pKa I 3.6) is decreased to
8.0(the pKa of clonidine) b/c of its direct attachment to the ring Thus,
clonidine exist in nonionized form at physiologic PH, crosss BBB.

Cl

H
N
clonidine
NH

Cl
N

108
 Guanafacine & guanabenz
• Open ring imidazoline
• The 2,6-dichlorophenyl moiety found in clonidine is
connected to a guanino group by two atom bridge
• SAR studies showed that the imidazoline ring was not
necessary for activity in this class
• But the phenyl ring required atleast one ortho Cl or CH3 group

Cl Cl

H H
N NH2 N NH2
N

NH O NH
Cl Cl
guanabenz guanafacine

109
 TIZANIDINE
• is a centrally active muscle relaxant analoge of clonidine that
is approved for use in reducing spasticity associated with
cerebral or spinal cord injury.

• Its mechanism of action for reducing spasticity suggests

presynaptic inhibition of motor neurons at the 2 -adrenergic
receptor sites, reducing the release of excitatory amino acids
and inhibiting facilitatory ceruleospinal pathways, thus
resulting in a reduction in spasticity.

110
• Tizanidine only has a small fraction of the antihypertensive
action of clonidine, presumably because of action at a
selective subgroup of  2C-adrenoceptors, which appear to be
responsible for the analgesic and antispasmodic activity of
imidazoline  2- agonists

APRACLONIDINE AND BRIMONIDINE

111
 Apraclonidine

 When applied topically, it reduces intraocular pressure (2-

mediated  in the formation of aqueous humour) with

minimal or no effects on CVS.

 It does not cross the BBB.

 Therapeutic use:
 Short-term adjunctive therapy in glaucoma

 To control or prevent elevations in intraocular pressure

 Brimonidine
 Similar in actions and use as apraclonidine
 Unlike apraclonidine, it can cross the BBB and can
produce hypotension and sedation, although these
CNS effects are slight compared to those of
clonidine.
 Methyldopa
• is structurally unrelated to clonidine
• is antihypertensive  2 agonist
• Acting via its active metabolite, -methyl NE

114
 β1 adrenergic receptor agonist
• Dobutamine can viewed as an analogue of dopamine in which
1-(methyl)-3-(4’-hydroxyyphenyl)propyl substituent has been pl-
aced on the amino group.
 This substitution gives a compound possesses an asymmetric center.
 (-)-isomer is a potent agonist at 1 receptors
 (+)-isomer is a potent 1 receptor antagonist, which can block the effects of (-)-
dobutamine.
 Both isomers appear to be full agonists at 1 .
• More prominent inotropic than chronotropic effects compared to isoproterenol
• Treatment of Cardiogenic shock

115
2-agonist phenylethylamines
• Most -selective adrenergic agonists used primarily as
– Bronchodilators in asthma & other constrictive pulmonary conditions
• Examples are
– Albutrol, Pirbuterol, Terbutaline
» Are non-catechol 2 selective agonists
» Can be used orally
» Short acting

OH
OH
H H
N N N

OH OH

Albuterol Pirbuterol
OH OH

Terbutaline

116
 -adrenergic agonists cont.
Other example is Biolterol
• is a prodrug for colterol
– The ester group is hydrolyzed by esterase to
liberate the active drug
• Has high lipophilicity and prolonged duration of action

O
OH
H OH
N H
O O N
HO
Esterase

O Colterol
HO
Bitoltetrol
H3C

117
 Long acting 2-agonist

Indacaterol
• The newest bronchodilator, approved for use in chronic obstructive pulmonary
disease.
• Indicaterol has a much longer duration of action of 24 hours, permitting once-
daily dosing

118
 Salmeterol.
• A b2-agonist with a slow onset and extended duration of
action is salmeterol.
• Salmeterol has the same phenyl ring substitution R3 as
albuterol but also an unusually long and lipophilic group R1 on
the nitrogen.
• Salmeterol is approximately 50-fold more selective than
albuterol for the b2-receptor. Substantial evidence indicates
that its long duration of action results from a specifi c binding
interaction (“anchoring”) of the phenyl
• group at the end of the extended lipophilic side chain with a
specific region of the b2-receptor, affording salmeterol a
unique binding mechanism
• Salmeterol is usually prescribed for severe persistent asthma
following previous treatment with a short-acting b-agonist,
such as albuterol.
119
 Formoterol

• has 3′-formylamino and 4′-hydroxy ring R3 substitution

pattern but also an alkoxyphenylethyl lipophilic group R1 on
the nitrogen, similar to ritodrine.

• Although it is less lipophilic (logP = 1.6) than salmeterol, it has

a 12-hour duration of action similar to that for salmeterol.

• It is administered as an inhaled dry powder, because it is

unstable to heat and moisture.

• Arformoterol is the single R,R active stereoisomer.

Arformoterol and Formoterol have a faster onset of action
than salmeterol as a result of lower lipophilicity 120
 Mixed acting sympathomimetics
• Have weak actions on AR but sufficiently resemble NE to be
transported into nerve terminals by uptake 1.
• Inside the nerve terminals, they are taken up into vesicles, displace the NE which
escapes into the cytosol

121
 Actions
 Include bronchodilatation, raised arterial pressure, peripheral
vasoconstriction, increased heart rate and force of
myocardial contraction, and inhibition of gut motility.

 They have important central actions, which account for their

significant abuse potential and for their limited therapeutic
applications

 These drugs are no longer used for their peripheral

sympathomimetic effects
Ephedrine
• Is a natural product isolated from several species of the genus Ephedra
• Does not have any substituents on the phenyl ring
– It is orally active as it is not a substrate for COMT
• Lacking hydrogen bonding phenyl substituents
– It is less polar and can easily cross BBB compared to catechols
• Isomer with 1R, 2S absolute configuration has
– Direct activity on the receptors, both  & 
– Also has an indirect component

OH

NHCH3
* *
Ephedrine (1R:2S &)
Pseudoephedrine (1R:2R & 1S:2S) * Chairal centers
CH3

123
Methyl substituted phenylethylamines
• S(+)Amphetamine and S(+)Methamphetamine
– Both lack ring substituents and side chain hydroxyl groups:
• are sufficiently lipophylic to cross the BBB
– Cause dramatic CNS stimulation
» Are drugs of abuse

H
NH2 N CH3
* *

CH3 CH3

Amphetamine Methamphetamin

124
 Adrenergic
Blocking agents
 Non-Selective -AR Antagonists
- Haloalkylamines derivatives

• β-haloalkylamine that alkylate α-receptors

• Since the alkylation is irreversible, the α-blockage is long lasting
• Restoration of cellular responsiveness to agonists requires the
synthesis of new receptors.

Cl
N
O

Phenoxybenzamine,
Dibenzyline®

126
 Phenoxybenzamine
 Therapeutic Uses
 Treatment of pheochromocytoma
Treat patients in preparation for surgery
Prolonged treatment in patients with inoperable or
malignant pheochromocytoma

 Toxicity and adverse effects

 Postural hypotension accompanied by reflex
tachycardia, reversible inhibition of ejaculation. It is
found to be mutagenic in experimental studies.
 Imidazoline derivatives
• Similar to imidazoline α agonsts; naphazoline, tetrahydrozoline,
and xylomethazoline.
• The type of the group attached to the imidazoline ring dictates
whether an imidazoline is an agonist or antagonist.
• The two representative imidazoline are phentolamine and
tolazoline

• Short-term control of hypertension in patients with pheochromocytoma

128
 Selective α1 antagonists

Prazosin, doxazosin, terazosin, tamsulosin Afluzosin and silodosin

• prazosin is antihypertensive agent, as are tetrazosin and doxazosin

• prazosin, doxazosin ,terazosin and afluzosin contain a 4-amino-6,7-

dimethoxyquinazoline ring system attached (except afluzosin) to a

piperazine nitrogen.

• Afluzosin is connected to propyelenediamino moiety.

• The nonquinazoline benzensulfonamides : Tamsulosin and silodosin
129
• The only structural difference of drugs having quinazoline ring
with piperazine moiety is group attached to the other nitrogen of.
• The difference in this group affords dramatic difference in some
pharmacokinetic properties
Ex. Terazosin & doxazosin have long half-life, which permit once a
day dosing O
R
O

N R prazosin

H3CO N N O
terazosin

N
H3CO O

doxazosin
NH2

H
H2NO2S N
O

OCH2CH3
Tamsulosin
H3CO

130
• Prozosin absorbed orally with bioavaillability of 50-70 %,
extensively protein bound (95%)
 It has a duration of action of 7 to 10 hours in the treatment of
hypertension

 Terazosin has a better bioavaillability (>90%).

Duration of action extends to 18 hours, which
enables once per day administration
 Duration of action of doxazosin extends to 36 hrs.
• Prazosin, Terazosin and Doxazosin are used to treat
hypertension.

• Tamsulosin , Silodosin (structurally unrelated to

prazosin ) and afluzosin are more selective for α 1
adrenoceptors in prostate glands.
 Hence, alleviate the symptoms of benign prostatic
hyperplasia (BPH)
 Adverse effects

 First-dose effect; marked postural hypotension,

and syncope (Most Quinazolines)
 Impaired ejaculation (drugs indicated for BPH)
 Yohimbine
 Indolealkylamine alkaloid which is selective competitive
antagonist of 2-AR

 It readily enters the CNS, and acts to increase BP and heart rate;
it also enhances motor activity and produces tremors
 has been used to treat male impotence & postural hypotension
-AR Antagonists
 Adrenergic blocking agents

• A derivative of isoproterenol in which the catechol hydroxyls are

replaced by chlorines
• Dichloro isoproterenol (DCl) is an example
• DCl has no clinical utility, partial agonst
• replacement of the 3,4-dichlorosubstituent with a carbon bridge
– Affords a naphthylethanolamine derivative (pronethalol)
• A clinical candidate,however, it was withdraw from clinical
testing as it caused thymic tumor in mice

OH
OH
CH3 CH3
H
Cl H N
N
CH3
CH3

Cl DCI Pronethalol

136
Structure activity relationship of  adrenergic blockers

• Introduction of oxy methylene bridge (OCH 2) into arylethanolamine

structure of pronethalol
– Gives propranolol

• In general aryloxy propanolamines are more potent than the

corresponding arylethanolamines
– Most -blockers currently used clinically are aryloxypropanolamines

– Increasing length of the side chain Was assumed to prevent proper binding to
the receptor
• Molecular modeling showed that side chain of aryloxypropanolamines
– Can adopt a conformation that places the OH and amine groups into
approximately the same position

137
 CH3

OH
O
H N
H CH3
N CH3
OH
CH3

(Propranolol)
Arylethanolamine
Aryloxypropanolamine

Superimposition Conformational change

O OH
H
N CH3

CH3

138
d.
d. Adrenergic
AdrenergicReceptor
ReceptorBlockers
Blockers
OH H
4
HO N
H
-Selective Blockers
-Selective Blockers
HO

OH H OH H
HO N Cl N

HO Cl

Isoproterenol, Isoprenaline® Dichloroisoproterenol, DCI

6
OH H OH H
HO N O N

HO
6 Propranolol, Indral®
Colterol
OH H OH
6 N O N HO 6
OH H OH H
N N S N
O O
H N N
O

Pindolol, Visken® Timolol, Timoptic® Nadolol, Corgard®

139
• Propranolol
– Discovered in an attempt to get a drug for the treatment of angina
pectoris
– At the clinical trial stage
• It demonstrated that it has an antihypertensive property
• A new series of phenyloxypropanolamines emerged
• Such as atenolol, metoprolol, acebutolol etc that are 1 selective
• Labetalol (phenylethanolamine deriv.) & carvedilol with mixed (/) activity
– 1 selective ones (atenolol, metoprolol)
• Inhibited sympathetic cardiac stimulation
• Have no effect on lung muscles (2 receptors)

NH2
O O

O NH O NH

Atenolol OH Metoprolol OH

140
 bb11-Selective
-SelectiveBlockers
Blockers 6

OH H OH H
O N O N
NH2

O N O
H
Practolol, Eraldin® Atenolol, Tenormin®

OH H
OH H
O N
O N
O
O N
H O

Acebutolol, Sectral® Metoprolol, Lopresor®

141
Mixed / inhibitory agents
Labetalol (phenylethanolamine derivative)
• is a competitive inhibitor of both 1 & 2 receptors & at 1 adrenergic receptor
– is a more potent -antagonist than -antagonist

– It has two asymmetric carbon atoms (1 & 1’) mixture of four isomers
• It is this mixture that is used clinically
• The different isomers however possess different  & -antagonistic activity

– The -blocking activity resides solely in the (1R, 1’R)isomer

– The 1antagonistic activity is seen in the (1S, 1’R)- and (1S, 1’S isomers)

» With the (1S, 1’R)- isomer possessing the greater activity

– Used in the management of hypertension due to -receptor blocking effects leading to vasodilation
and -receptor blocking effects that prevent tachycardia usually associated with vasodilation
OH
H
N 1'
1

CH3
HO
142
CONH2 Labetalol
 Carvedilol
– Like labetalol is a -blocker that possesses 1-adrenergic receptor
blocking activity
• Only the (S)-enantiomer possesses the -blocking activity
• Both enantiomers are antagonists for the 1-adrenergic
receptor
• Has antioxidant and antiproliferative effect on vascular smooth
muscle.
OCH3

O
*
O N
H
OH

N
H
Carvedilol

143