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–8–
Central Nervous System Stimulants

A huge number of physiologically active substances exhibit stimulatory action on the cen-
tral nervous system (CNS); however, the number of drugs used for this purpose in medi-
cine is extremely limited. Substances that increase vigilance and reduce the need for sleep
are considered as CNS stimulants or psychostimulants. In other words, there are drugs
capable of temporarily keeping one awake, elevating mood and maintaining adequate per-
ception of reality, reducing outer irritability and the feeling of fatigue, and elevating the
physical and mental capacity of work.
Some CNS stimulants such as amphetamines and methylphenidate are sometimes used
for elevating mood in patients with depression. However, unlike the antidepressants exam-
ined in Chapter 7, these compounds only elevate the level of excitement of the CNS and
cannot affect depression, and therefore the terms antidepressant and psychostimulant
should be differentiated.
CNS stimulants can be classified as: Psychomotor stimulants: compounds that display
a stimulatory effect primarily on brain functions and which activate mental and physical
activity of the organism. They are made up of: methylxanthines (caffeine, theophylline,
pentoxifyllin), amphetamines (dextroamphetamine, methamphetamine), and also
methylphenidate and pemoline. Respiratory stimulants or analeptics: compounds, which
cause certain activations of mental and physical activity of the organism, and primarily
excite the vasomotor and respiratory centers of the medulla (doxapram, almitrine).Drugs
that suppress appetite or anorectics: drugs that activate mental and physical activity of the
organism, but primarily accentuate the excitatory center of satiation in the hypothalamus
(phentermine, diethylpropion).In order to increase mental capability, nootropics — drugs
that increase the functional state of the brain — are sometimes used, the effect of which is
associated with blood flow and metabolism of the brain.

8.1 PSYCHOMOTOR STIMULANTS

8.1.1 Methylxanthines

Caffeine: Caffeine, 1,3,7-trimethylxanthine (23.3.6), is the most widely used CNS stimu-
lant. It is an alkaloid in tea leaves (Thea sinensis), in coffee beans (Coffea arabica), in

117
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118 8. Central Nervous System Stimulants

cocoa beans (Theobroma cocao), in cola seeds (Cola acuminata), and in other plants
whose synthesis will be described in Chapter 23, “Drugs for treating pulmonary diseases.”
O CH 3

CH 3 N N

O N N
CH 3
23.3.6

A cup of coffee can contain 50–150 mg of caffeine, and cola drinks can have 35–55 mg.
Theophiline,1,3-dimethylxanthine, a principal, characteristic alkaloid of tea, and theo-
bromine, 3,7-dimethylxanthine (23.3.19), a principal alkaloid of cocoa, are among a num-
ber of methylxanthines. In small doses, caffeine is a relatively weak psychostimulant and
is used for increasing awareness as well as for relieving headaches associated with blood
flow disorders of the brain. Caffeine has a stimulatory effect on the respiratory and vaso-
motor centers, and it stimulates centers of the vagus nerve. It has a direct stimulatory effect
on the myocardium, and in large doses can cause tachycardia and arrhythmia.
Caffeine displays dual action on the level of blood pressure. It raises blood pressure by
a central mechanism of stimulating the vasomotor center, but lowers it by facilitating the
widening of blood vessels by directly affecting the smooth muscle of the vascular walls.
In a person with regular blood pressure, caffeine causes practically no changes; however,
introducing it into a patient with hypotension causes the blood pressure to rise (normalize).
Secretion of stomachic glands increases under the influence of caffeine. It is believed that
the stimulatory effect of caffeine is connected to its ability to competitively bind to adeno-
sine receptors, a factor which lowers the excitatory processes in the brain. Replacing them
with caffeine leads to a stimulatory effect, since methylxanthines and adenosine cause
opposite effects. According to another point of view, by inhibiting phospodiesterase, caf-
feine increases the concentration of cyclic adenosinemonophosphate (cAMP), which
serves as a second messenger by which physiological effects of several biologically active
substances are carried out. In particular, glycogenolic processes are strengthened under the
influence of cAMP, and metabolic processes are stimulated in various organs and tissues,
the CNS included.
Caffeine is used for stimulating metal activity, for fatigue, migraines, and hypotension.
Synonyms of caffeine are not popular. They are cafecon, coffan, and a few others.

8.1.2 Amphetamines, methylphenidate, and pemoline

Amphetamines are powerful synthetic psychostimulants with a high potential of addiction.

They increase vigilance and the ability to concentrate, temporarily elevate mood, and stim-
ulate motor activity. However, depending on the dosage and more importantly on the per-
son’s personality, they can cause various levels of euphoria, raise blood pressure, and
facilitate contraction of the sphincter of the urinary bladder as well as facilitate the devel-
opment of mydriasis.
Prolonged amphetamine use often leads to irritability, insomnia, and hyperhidrosis.
Changing drugs can result in depression. Attempting to overcome the depressive state by
using higher doses of the same amphetamines leads to a vicious cycle of addiction and
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8.1 Psychomotor Stimulants 119

dependence. Taking even higher doses of the drug causes euphoria, hallucinations, and
other psychotic effects with symptoms very similar to the clinical symptoms of the para-
noid form of schizophrenia.
It is believed that the mechanism of action of amphetamines lies in their ability to
release epinephrine (adrenaline) and dopamine from presynaptic nerve endings, which
stimulate the corresponding receptors in the CNS. It is also possible that they reduce neu-
ronal uptake of amines as well as inhibit their degradation by monoaminoxidase (MAO).
Characteristic of this series of compounds is the effect on the respiratory center, on the
satiation center located in the hypothalamus, which leads to suppression of feelings of
hunger, thus allowing analog of the examined compounds to be used as anorectics.
Together with the CNS, compounds of this group affect the nervous system. They indi-
rectly stimulate α- and β - adrenoreceptors. The adrenomimetic properties of these com-
pounds are similar to the properties of norepinephrine (noradrenaline); however, they are
quite inferior to them in terms of activity.
In terms of chemical structure, amphetamines are very close to epinephrine (adrenaline),
norepinephrine (noradrenaline), and dopamine, differing in the absence of a hydroxyl
group in the aromatic ring and in the aliphatic chain.
HO HO
CH3
CH2 C NHR 1 HO CH CH2 NHR1 HO CH 2 CH2 NH2
R
OH

amphetamines epinephrines dopamine

Amphetamines are used in treating narcolepsy, to increase the capacity to work, in treating
attention-deficit disorder in children, and also in treating obesity. The effects of amphetamines
can be potentiated by tricyclic antidepressants, MAO inhibitors, acetozolamide, cocaine, fura-
zolidone, propoxyphene, sodium bicarbonate, and other drugs which alkylize urea. At the
same time, antagonists of amphetamines are drugs which acidify urea: ascorbic and gluta-
minic acid, phenothiazines, haloperidol, methenamine, lithium drugs, and fruit juices.

Dextroamphetamine: Dextroamphetamine, D-2-amino-1-phenylpropane (8.1.2.2), is synthe-

sized by various methods. One of them consists of uses of the Leucart reaction, in particular,
the reaction between methylbenzylketone and ammonium formate, giving the formamide
(8.1.2.1), which is hydrolyzed to 2-amino-1-phenylpropane (8.1.2.2) by hydrochloric acid [1].
An analogous method has been suggested using formamide instead of ammonium formate [2].
O CH3 CH3
HCOONH4 HCl
CH2 C CH 3 CH2 CH NHCHO CH2 CH NH 2

8.1.2.2
8.1.2.1

The other method consists of monoalkylation of ammonia using 2-chloro-1-phenyl-

propane [3].
CH 3 CH 3
NH 3
CH 2 CH Cl CH 2 CH NH 2

8.1.2.2
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120 8. Central Nervous System Stimulants

2-Amino-1-phenylpropane (8.1.2.2) is also synthesized in a Hofmann reaction from

α-benzylpropionic acid amide [4,5].

CH 3 CH 3
NaOBr
CH 2 CH CONH 2 CH 2 CH NH 2

8.1.2.2

The product of either of the outlined methods, 2-amino-1-phenylpropane (amphetamine)

is separated into isomers using D-tartaric acid, and separating the necessary dextroam-
phetamine, D-2-amino-1-phenylpropane (8.1.2.2) [6,7].
Dextroamphetamine is a powerful stimulant of the nervous system that manifests its
effects by releasing dopamine and norepinephrine from presynaptic nerve endings, thus
stimulating central dopaminergic and noradrenergic receptors. In certain doses it strength-
ens the excitatory process in the CNS, reduces fatigue, elevates mood and the capacity to
work, reduces the need for sleep, and decreases appetite.
Dextroamphetamine should be used with caution and only upon medicinal indication in
treating narcolepsy, consequences of encephalitis, and other illnesses accompanied by apa-
thy, drowsiness, asthenia, for temporary increase of physical and mental capacity, in treat-
ing attention deficit disorder in children, and in treating obesity.Synonyms of this drug are
D-amphetamine, dexamphetamine, dexalone, tempodex, zenidex, and many others.

Methamphetamine: Methamphetamine, (⫹)-N-α-dimethylphenylethylamine (8.1.2.3),

can be synthesized by the reduction of (⫺)-ephedrine by hydrogen using a palladium on
carbon catalyst [8].
CH 3 CH 3
H 2 / Pd C
CH CH NHCH 3 CH 2 CH NHCH 3
OH
8.1.2.3

Another way of making methamphetamine is by the reduction of methylbenzylketone by

hydrogen in the presence of methylamine [9].
O CH 3NH 2 / H 2 CH 3
CH 2 C CH 3 CH 2 CH NHCH 3

8.1.2.3

It possesses the same properties as dextroamphetamine and is used for the same indica-
tions.Synonyms of this drug are peritin, filopon, desoxyn, methampex, and others.

Methylphenidate: Methylphenidate, the methyl ester α-phenyl-2-piperidilacetic acid

(8.1.2.6), is synthesized in the following manner. Arylation of benzylcyanide by 2-chloro-
pyridine in the presence of a base gives α-phenyl-α-(2-pyridil) acetonitrile (8.1.2.4). Sulfuric
acid hydrolysis of the nitrile group and subsequent esterification with methanol gives the
methyl ester of α-phenyl-α-(2-pyridylacetic acid) (8.1.2.5). The pyridine moiety is reduced
into a piperidine by hydrogen over platinum, giving methylphenidate (8.1.2.6) [10–12].
1. H2SO4 / H 2O
CN 2.CH 3OH / HCl
CH 2 CN + CH
N Cl N

8.1.2.4
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8.2 Respiratory Stimulants or Analeptics 121

O OCH 3 O OCH 3
H 2 / [Pt]
CH CH
N N
8.1.2.5 H
8.1.2.6

Methylphenidate is a CNS stimulant similar to amphetamine; however, in usual doses it

has a more expressed action on mental activity rather than physical or motor activity. In
therapeutic doses it does not raise blood pressure, respiratory rate, or increase heart rate.
All of these effects as well as a number of others are associated with general excitement
of the CNS. Tremor, tachycardia, hyperpyrexia, and a state of confusion can result from
using large doses. It is used in treating moderate depression and apathetic conditions, and
also as an adjuvant drug for treating attention deficit disorder in children.Synonyms of this
drug are meridil, ritalin, and others.

Pemoline: Pemoline, 2-amino-5-phenyl-2-oxazolin-4-one (8.1.2.7), is synthesized by the

condensation of the ethyl ester of mandelic acid with guanidine [13,14].

OH NH O
CH COOC 2H 5 + H 2N C NH 2
O N NH

H
8.1.2.7

Pemoline is a structurally unique CNS stimulant that exhibits minimal sympatomimetic

effects, and possesses the same pharmacological properties as amphetamines and
methylphenidate, yet it has less potential to cause addiction than other CNS stimulators. It
enhances vigilance and motor activity, and causes weak euphoria, which is possibly linked
to an increase in dopaminergic transmissions in CNS structures.
Pemoline is used for narcolepsy and for relieving drowsiness, as well as in treating
attention-deficit disorder in children. Synonyms of this drug are tradon, deltamine, volital,
phenoxazole, antimeran, cylert, and others.

8.2 RESPIRATORY STIMULANTS OR ANALEPTICS

Analeptics are drugs that have a stimulatory effect on the respiratory and vasomotor
centers of the medulla. Analeptics are primarily used as antagonists in depressant drug
overdose (hypnotics, narcotics). Having a relatively small range of therapeutic action, they
can stimulate other parts of the CNS even in minor overdoses, causing a number of unde-
sirable side effects such as stimulation of the cardiovascular system, hyperreflexia, vomit-
ing, and seizures.

Doxapram: Doxapram, 1-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone

(8.2.4), is synthesized in the following manner. Diphenylacetonitrile in the presence of
sodium amide is alkylated with 1-ethyl-3-chlorpyrrolidine, giving (1-ethyl-3-pyrrolidinyl)
diphenylacetonitrile (8.2.1). Acidic hydrolysis of the nitrile group gives (1-ethyl-3
pyrrolidinyl)diphenylacetic acid (8.2.2). Reacting this with phosphorous tribromide
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122 8. Central Nervous System Stimulants

(thionyl chloride, thionyl bromide, acetic anhydride) leads to rearrangement with an open-
ing of the pyrrolidine ring and the subsequent closing of the pyrrolidinone ring, forming
1-ethyl-4-(2-bromoethyl)-3,3-diphenyl-2-pyrrolidinone (8.2.3). Substitution of the
bromine atom with a morpholine group gives doxapram (8.2.4) [15–18].

Cl
NaNH 2 H 2SO4 PBr3
C C N + C C N C COOH
H N
C 2H 5
N N
C 2H 5 C 2H 5
8.2.1 8.2.2

CH 2 CH 2 Br H N O CH 2 CH 2 N O

O O N
N
C 2H 5 C 2H 5

8.2.3 8.2.4

Doxapram increases the rate and depth of respiration. It is used for post-anesthetic respi-
ratory depression, and for respiratory depression caused by drug use. Synonyms of this
drug are doxapril, dopram, and others.

Almitrine: Almitrine, 2,4-bis (allylamino)-6-[4-[bis-(p-fluorophenyl)methyl]-1-piper-

azinyl]-s-triazine (8.2.6), is synthesized by reacting 1-[bis-(p-fluorophenyl)methyl]piper-
azine with cyanuric chloride, which gives 2,4-dichloro-6-[4-[bis-(p-fluorophenyl)
methyl]-1-piperazinyl]-s-trazine (8.2.5). Reacting this with allylamine gives almitrine
(8.2.6) [19–22].
F F

Cl Cl
N NaOH N H 2N CH 2 CH CH 2
CH N N H + Cl N CH N N N
N N
Cl Cl
8.2.5
F F

NH CH 2 CH CH 2
N
CH N N N
N
NH CH 2 CH CH 2
8.2.6
F

Almitrine, like doxapram, increases the rate and depth of respiration. In addition, it is
believed that it redistributes pulmonary blood circulation, increasing it in alveoli, which
leads to relatively better pulmonary ventilation. It has a more prolonged effect than
doxapram.Synonyms are vectarion, duxil, and others.
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8.3 Appetite Suppressants or Anorectics 123

8.3 APPETITE SUPPRESSANTS OR ANORECTICS

A group of drugs structurally related to amphetamines that suppress appetite and which are
used in treatment of obesity are called analeptics.
Compounds of this group exhibit a range of pharmacological and toxicological action
analog to that of amphetamines, and are used as adjuvant drugs in the treatment of obe-
sity,which is accomplished through an individually structured program of limiting caloric
intake. Not one of the substances used exceeds amphetamines in terms of activity; how-
ever, the lesser likelihood of dependence makes its use preferable. The mechanism of
action of these drugs is similar to that of amphetamines. They activate satiation centers of
the hypothalamus, thus reducing appetite. Anorectics can enhance the effects of narcotics,
barbiturates, alcohol, and other CNS depressants.

Phentermine: Phentermine, α,α-dimethylphenylethylamine (8.3.4), differs from amphet-

amine in the presence of an additional methyl group in the α-position of the amino group.
It is synthesized from benzaldehyde, the condensation of which with 2-nitropropane gives
carbinol (8.3.1). Reduction of the nitro group of this product gives 2-amino-2-methyl-1-
phenylpropanol (8.3.2). The hydroxyl group is replaced with a chlorine atom upon reac-
tion with thionyl chloride, giving 2-amino-2-methyl-1-phenylpropylchloride (8.3.3).
Reducing this with hydrogen using a palladium on calcium carbonate catalyst gives phen-
termine (8.3.4) [23,24].

CH 3 CH 3 CH 3
H 2 / Raney Ni SOCl2
CHO + H C NO2 CH C NO2 CH C NH 2
CH 3 OH CH 3 OH CH 3

8.3.1 8.3.2

CH 3 H 2 / Pd CaCO3 CH 3
CH C NH 2 CH 2 C NH 2
Cl CH 3 CH 3

8.3.3 8.3.4

The action of this drug consists of the activation of the satiation center of the hypothala-
mus and the reduction of appetite, which by limiting caloric intake leads to weight
loss.Synonyms of this drug are ionamin, linil, lipopill, teramine, and others.

Diethylpropion: Diethylpropion, 1-phenyl-2-diethylaminopropanon (8.3.6), is synthe-

sized by the bromination of propiophenone into α-bromopropiophenone (8.3.5) and the
subsequent substitution of the bromine atom with a diethylamino group [25,26].
O O O
Br2 HN(C 2H 5)2
C CH 2 CH 3 C CH CH 3 C CH CH 3
Br N(C 2H 5)2

8.3.5 8.3.6

Diethylpropion possess basically the same pharmacological properties as amphetamines

and is used in treating obesity by limiting caloric intake.Synonyms of this drug are
amphepramone, anorex, adiposon, regenon, tenuate, tepanil, and others.
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124 8. Central Nervous System Stimulants

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