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Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 45
C. Amphetamine: It is racemate of dextroamphetamine and methamphetamine
CH — CH — NH
22
CH
3
CH — CH — NH
23
CH
CH
3
Dextroamphetamine Methamphetamine
Fig. 2.57
2.3.7 SAR of Phenylethanolamine Derivatives/Direct Acting Agonist
H
N—R
1
OH
R
2
a
b
2¢
3¢
R
3
Para
4¢
5¢
6¢
1¢
1
Aryl ring
substitution
Meta
Terminal group
2
Fig. 2.58
Substitution are the following
Derivatives R
1
R
2
R
3
Adrenergic receptor
activity
1. Nor-epinephrine H H 3’, 4’-diol α
1
α
2
β
1
2. Epinephrine CH
3
H 3’, 4’-diol β
1
> α
1
α
2
β
1
3. Isoproterenol — CH(CH
3
)
2
H 3’, 4’-diol β
1
+ β
2
4. Terbutaline — C(CH
3
)
3
H 3’, 5’-diol β
2
> β
1
5. Ephedrine CH
3
CH
3
H α
1
, α
2
, β
2
6. Salbutamol — C(CH
3
)
3
H 3’-methylhydroxy β
2
4’-methylhydroxy
7. Phenylephrine — CH
3
H 3’-OH α
1. R
1
substitution on terminal nitrogen group
(i) Terminal nitrogen group substitution plays a vital role in the adrenergic receptor activity. It
has been shown that increase in the size of R
1
results in the decrease of the selective activity
at α receptors followed by increase in the β-adrenergic activity.
(ii) The activity at both α and β receptors shown to be maximal when R
1
is methyl substitution,
e.g., epinephrime.
(iii) It has been shown that if R
1
becomes larger than butyl group affinity for α
1
-receptors
returns but does not exhibit Intrinsic activity.
46 A Textbook of Medicinal Chemistry
2. R
2
-substitution
(i) Presence of small alkyl groups such as methyl or ethyl at α to the basic nitrogen atom. Such
substitution exhibits slow metabolism by monoamine oxidase (MAO) enzyme, but shows
little effect on duration of action in catecholamines.
(ii) Introduction of ethyl (C
2
H
5
) group at position 2, diminish α-adrenergic activity far more
than β-selectivity.
(iii) Carbon atom at position No. 2 and its substitution plays as asymmetric center into this
molecule which produces a pair of diastereomers that exhibit significantly distinct biological
as well as chemical properties.
3. Substitution on Aromatic Ring (R
3
)
(i) Aryl ring is essential for activity.
(ii) The nature of 3’, 4’-dihydroxy substituted Aryl ring provides excellent receptor activity for
both α and β receptors.
(iii) Other substitutions are also possible that enhance oral activity and show β
2
selective activity
such as 3’-hydroxymethyl and 4’-hydroxymethyl substitution in salbutamol. Such type of
substitution also resist COMT mechanism.
(iv) At least one of the groups must be capable of forming hydrogen bond at the receptor site and
retain the β-adrenergic activity e.g. Ritodrine.
CH
3
H
N
OH
HO
Fig. 2.59: Ritodrine.
(v) Introduction of 3’-hydroxy group only, however, the activity is reduced at α-site and almost
eliminated at β-site thus affording selective α-adrenergic agonist for example pheylephrine
and metaraminol.
NH — CH
3
OH
HO
CH
3
NH
2
HO
OH
Phenylephrine
Metaraminol
Fig. 2.60
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 47
2.3.8 SAR of Indirect Acting Agonist/Arylethylamine Derivatives
C—C—NH—R
3
CH
3
R
1
H
b
a
R
2
Terminal
nitrogen
(favored)
Aryl ring lack of
3 , 4 -hydroxy
group
¢¢
Fig. 2.61
Substitutions are the following:
Derivatives R
1
R
2
R
3
1. Phenyl propanolamine OH H H
2. Amphetamine H H H
3. Metamphetamine H H CH
3
4. Phentermine H CH
3
H
(i) The above mentioned figure of pharmacophore indicates that indirect acting adrenergic agonist
do not contain the phenolic hydroxyl groups at 3’, 4’ position. Lack of these ionic groups
potentiate the oral absorption and increase the penetration in CNS.
(ii) The phenolic hydroxyl groups may or may not be present in indirect acting compounds.
Those compound without this alcoholic hydroxyl groups are less polar and pass more readily
through BBB (blood brain barrier) and exhibit greater CNS stimulation.
(iii) The phenylic group may be replaced by other groups, i.e., cycloalkyl or alkyl groups which
results in change of the activity.
(iv) Propylhexedrine is an analogue of amphetamine in which aryl ring is replaced by cyclohexane
ring. This effect still possesses the adrenergic activity. This drug is used for vasoconstriction
and decongestant effect.
CH
3
CH
3
Fig. 2.62: Propylhexedrine.
2.3.9 Adrenergic Agents
1. Epinephrine (Adrenaline) : Epinephrine is also known as adrenaline. It has potent stimulatory
effect on both α and β receptors. It is a light sensitive drug and for avoiding the oxidation it is kept
with the addition of reducing agent sodium bisulphite. Ephedrine is used in the treatment of open
48 A Textbook of Medicinal Chemistry
angle glaucoma, in nasal congestion, and also for enhancing the activity of local anaesthetics.
Ephedrine is obtained from adrenal gland tissue of livestock as well as from synthetic route.
Synthesis:
HO
HO
C—CH —Cl
2
O
H CNH
32
HO
HO
CO — CH — NHCH
23
HO
HO
CH — CH — NHCH
23
OH
Ephedrine
H | Raney-Ni
(Reduction)
2
Fig. 2.63
2. Nor-Epinephrine: Nor-epinephrine is also known as nor-adrenaline. It is a primary
neurotransmitter and produces and releases by adrenergic neuron. Nor-epinephrine stimulate α-
adrenoceptors and activate of β
1
-adrenoceptors to produce cardiostimulatory effects.
3. Isoproterenol (Isoprenaline)
®
: Isoproterenol is highly selective to β-adrenoceptors due to presence
of bulky iso-propyl or tert butyl group at the terminal nitrogen atom of phenylethanolamine skeleton.
Isoproterenol is used in bronchospasma, asthma, cardiac block and in shock.
Synthesis:
HO
HO
C—CH —Cl+HN—CH
22
O
CH
3
CH
3
HO
HO
C — CH — NH — CH
2
O
CH
3
CH
3
HO
HO
CH — CH — NH — CH
2
OH
CH
3
CH
3
H|Pd—C
(Reduction)
of
(Carbonyl group)
2
Chloroaceyl pyrocatechol
Isopropylamine
Isoprenaline
Fig. 2.64
α-chloro-3’.4’-dihydroxy
acetophenone
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 49
4. Terbutaline (Bricanyl)
®
: Terbutaline is an important and selective direct acting β
2
-adrenoceptors
agonist. It stimulates smooth musles of bronchi β
2
- receptors and less effect on β
1
-receptors of the
heart. It is used in the treatment of bronchial asthma, chronic bronchitis, and other pulmonary
disease.
5. Salbutamol (Albuterol)
®
: Salbutamol is also known as Albuterol. It is a non-catechol selective
β
2
-adrenergic receptor agonist. Its R/S enantiomers have been shown that the (s) enantiomer may
be proinflammatory activity and is responsible for enhancing bronchial muscles contraction thus
show opposite bronchodilating effects of the (R)-enantiomer levoalbuterol. The recemic mixture of
albuterol has expressed broncholytic effects and increases the vital capacity of lungs. It is widely
used in the treatment of bronchial asthma and other illness of the respiratory tract.
Synthesis:
H COOC
3
HO
+Cl—C—CH —Br
2
O
CH C H
265
C(CH )
33
Methyl ester of
salicylic acid
H COOC
3
HO
—C—CH —Br
2
O
H—N
H COOC
3
HO
—CH—CH —N
2
OH
CH C H
265
C(CH )
33
H COOC
3
HO
—C—CH —N
2
O
CH C H
265
C(CH )
33
H COOC
3
HO
— CH — CH — NH — C(CH )
233
OH
Salbutamol
(Reduction) H | Pd — C
2
LiAlH
4
(Hydrolysis)
Bromoacetyl
chloride
N-benzyl-t-butylamine
Fig. 2.65
6. Ephedrine: Ephedrine is an alkaloid obtained from the plants extract ephedra sinica and ephedra-
equisetina. In the structure of ephedrine, two asymmetric atoms are present thus form four isomeric
forms. Pseudoepinephrine (d-isoephrine) is the stereoisomer of ephedrine. It is typical a non-
catecholamine sympathomimetics of mixed action. It stimulates both α- and β-adrenoceptors. Its
vasoconstructive properties are approximately 100-folds weaker than epinephrine but duration of
action is 10 times longer. Ephedrine is widely used in the treatment of bronchial asthma and in
allergic rhinitis condition. It is also used locally in ophthalmology for dilation of pupils.
50 A Textbook of Medicinal Chemistry
7. Imidazoline Sympathomimetics Derivatives: Imidazoline ring containing sympathomimetics:
naphazoline, oxymetazoline, xylometazoline and tetrahydrozoline which are used in the treatment of
rhinitics associated with cold, in chronic inflammatory condition, nose bleed, also used in the
treatment of laryngitis, sinusitis, etc.
Synthesis of Xylometazoline [Otrivin
®
]:
4-tert-butyl-2, 6-Dimethyl
benzylcyanide
CH CN + H N — CH — CH — NH
2 2 222
CH
3
CH
3
(CH ) C
33
CH
2
CH
3
CH
3
(CH ) C
33
N
H
|
N
X
y
lometazoline
(Cyclocondensation)
Ethylenediamine
Fig. 2.67
8. Amphetamine (Paredrine)
®
: Amphetamine and metamphetamine are the derivatives of
phenylisopropylamines. Both lack ring substituents, a side chain hydroxyl groups and thus behave
sufficiently lipophilic to cross blood brain barrier readily which causes dramatic CNS stimulation.
Clinically useful (S)-(+) amphetamine shows central appetite suppressant effects. Another function
of amphetamines is their psychostimulatory effects. Larger dose of amphetamines causes hallucination
and related mental condition similar to the paranoid schizophrenia.
Synthesis:
— CH — CH — NHOH
3
CH
3
OH
CH I
3
(Methylation)
—CH—CH—NH
2
CH
3
OH
Ephedrine
— CHO
CHNO
25 2
(Nitroethane)
—CH—CH—NO
2
CH
3
OH
[H] (Reduction)
Benzaldehyde
Fig. 2.66
Autonomic Nervous System Cholinergic Drugs and Adrenergic Agents 51
Synthesis: (Leucart Reaction)
CH —C—CH
23
O
CH — CH — NHCHO
2
CH
3
CH — CH — NH
22
CH
3
HCl
Methylbenzylketone
Dextroamphetamine
Fig. 2.68
2.3.10 Newer Drugs
1. Salmeterol (Servent)
®
: 2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenyl-butoxy) hexylamino]
ethyl} phenol
HO
NH
OH
O
OH
Fig. 2.69
Salmeterol serves as a long acting β
2
-adrenergic receptor agonist. It is suggested for the treatment
of asthma and (COPD) chronic obstructive pulmonary disease. It is 50 times more potent than
albuterol for β
2
-receptor activity.
2. Formoterol (Foradil)
®
: N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxy phenyl)-propane-2-
ylamino]ethyl]phenyl] formamide
N
H
OH
C=O
CH
3
O
HC
3
OH
N
H
Fig. 2.70: Formoterol.
Formoterol is long acting β
2
-receptor agonist like salmeterol. It is a mixture of (R.R.) (–) and
(S.S.)—(+)-stereoisomers. (R.R. (–) isomers are 1000 times more potent than (S,S) isomer. It has
faster onset of action. It is clinically prescribed for the treatment of asthma and COPD.
HCOONH
4
(ammonium formate)
52 A Textbook of Medicinal Chemistry
EXERCISE
1. Give the synthesis and uses of the following drugs.
a. Salbutamol
b. Amphetamine
c. Atropine
d. Neostigmine
e. Methacholine
f. Isoprenaline
2. Write the SAR of the following
a. Antimuscarinic agents
b. Adrenomimetics
3. Give the structures, nomenclature of any four antimuscarinic agents.
4. Give the general structure of muscarinic agonists and discuss their SAR.
5. Write a note on medicinal uses of anticholinesterage.
General Anaesthetics 53
3
General Anaesthetics
3.1 INTRODUCTION
General anaesthetic agents are those agents which are used to produce unconsciousness and loss of
perceptions in painful surgical operations. General anaesthetics is a class of CNS depressant drugs
which produce a partial or total loss of sense of pain with a controlled and reversible action of
central nervous system in order to perform more complicated surgical operations. A number of
chemical agents or drugs are clinically used as general anaesthetics such as inhalation anaesthetics,
alcohols, phenol derivatives, barbiturates, benzodiazepines and neurosteroids are acted on the allosteric
binding sites of GABA
A
receptors.
3.2 IDEAL CHARACTERISTICS OF GENERAL ANAESTHETICS
1. General anaesthetis are non-specific in action and do not interact with specific receptors.
2. They are used in high concentration and have access to all areas of the biological system.
3. They must be rapid in action and pleasant in behaviour induction of surgical anaesthesia.
4. After performing biological action, they should withdraw rapidly.
5. They must have adequate relaxation properties for skeletal muscles.
6. They must be potent enough to allow adequate oxygen supply in the mixture.
7. They should have wide margin of safety as well as nontoxicity.
8. They should have absence of adverse effects.
9. They must be non-inflammable and non-explosive in nature.
10. They should be economical.
54 A Textbook of Medicinal Chemistry
3.3 IMPORTANT PHYSIOLOGICAL PROPERTIES RESPONSIBLE FOR ENTRY OF
COMPOUNDS INTO BRAIN
1. The degree of ionization plays an important role into transport of drugs to cross blood brain
barrier at physiological condition (pH). It has been observed that non-ionized compounds
are more prone to penetrate easily.
2. Molecular size of the molecule must be less than 400 to increase penetration.
3. Lipophilic character of the molecule should be (log Po = 2 ± 0.31). Ideal for penetration into
BBB (blood brain barrier)
3.4 CONCEPTS OF MECHANISM OF ANAESTHESIA
1. Meyer-Overton Theory
This theory was concluded by Hans Meyer and Charles Overton in 1900. According to this theory,
potency of the compounds is directly related to its lipid solubility and oil-gas partition coefficient
with the reference of olive oil, octanol and other membranes like lipids.
According to this concept:
(i) All neutral lipid-soluble substances have depressant properties on neurons.
(ii) Anaesthetic properties are more pronounced in lipid rich cells.
(iii) Anaesthetic effects are gradually increased with increase in the partition coefficient.
Arguing against this theory however is the finding that all highly lipid soluble substances are not
capable of producing anaesthesia and moreover the protein drug interaction was the major problem.
2. Ion Channel Theory
General anaesthetics block ion channels by interacting with cellular membranes and reducing the
flow of Na
+
ions and enhancing the K
+
ions flow into the cells which leads to development of
anaesthesia.
3.5 MINIMUM ALVEOLAR CONCENTRATION (MAC)
It is defined as the concentration at 1 atmosphere in anaesthetic agents in the alveoli, which is
required to produce immobility in 50% of the patient subjected to surgical operation. Further increase,
1 to 1.3 MAC, will cause immobility in 99% of patients. At equilibrium the concentration of anesthetic
agents in the alveoli is equal to that in brain and it is this concentration in the brain at the site
responsible for pharmacological action.