Dr. Nadia Haress
Central Nervous System Stimulants
Drugs that produce stimulation of the central nervous system could be
classified into the following categories:
I.
II.
Analeptics.
Central Sympathiomimetics.
III.
Methylxanthines.
IV.
Antidepressants.
1
I- Analeptics
Analeptics = Respiratory stimulants

This is a group of agents with very limited range of use as high doses
cause seizures and convulsions, i.e., their analeptic dose (respiratory
stimulation) lies near their convulsive dose, due to their non-selectivity.

Mode of Action:
They cause direct stimulation of respiratory centres in the brain and also
involved in the regulation of blood flow.

Uses:
It is used for treatment of acute, postoperative or opioid-induced
respiratory depression (treatment of hypnotic intoxication).
Strychnine
2
Picrotoxin
Pentylenetetrazole

Strychnine, picrotoxin and pentylenetetrazole are used nowadays as only
pharmacological tools.
Nikethamide (Coramine)
N,N-Diethylnicotinamide
It stimulates respiratory centres in the brain. It had been used as antidote
in managing fun sedative-hypnotic drugs poisoning but they are now obsolete
for that use.
3
Doxapram (Dopram)
1-Ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone

Doxapram is the most safe analeptic as it has higher degree of selectivity
and shorter duration of action.

It is used in treatment of chronic pulmonary obstructive disease (CPOD).
4
II.
Central Sympathomimetic agents (Psychomotor
Stimulants)
A group of indirect sympathetic agonists were obtained by certain
structure modification of NE that led to production of compounds more resistant
to metabolism and more able to cross the blood-brain barrier (BBB). These
effects increase the proportion of central to peripheral activity and sometimes
referred to as central sympathomimetic agents. This central activity is
manifested as excitation, wakefulness, in addition, to anorexient effects. They are
divided into:
1- Phenylisopropylamine derivatives
2- Central sympathomimetics containing nitrogen (N) in cyclic structure
1-
Phenylisopropylamine Stimulants (Amphetamine and
Amphetamine Related Compounds)

They are -phenethylamine derivatives. Amphetamine is the prototype of
this group (lead compound).

Uses:
o Anoretics = anorexient in diet control
o Narcolepsy (irresistible attacks of sleep)
o Attention deficiency syndrome in hyperactive children
5

Mode of Action:
o Direct sympathomimetic action (direct -adrenergic receptor
stimulation).
o Indirect sympathomimetic action by enhancing ↑ the release of NE
and/or  uptake of NE. Also, it inhibits the uptake of serotonin
(5HT).

SAR:
meta
CH2
CH2

para
NH2

 -Phenethylamine is essential for activity.
 Branching with lower alkyl groups on the -carbon ↑ CNS activity while
higher alkyl groups (ethyl, n-propyl)  CNS activity.
 The -branchsing generates chiral centre and stereoselectivity of possible
enantiomers is apparent, e.g., the (+) dextro (S-isomer) of amphetamine is
400 times more active than the (-) levo (R-isomer), ↑ lipophilicity and
retards metabolism.
 Hydroxylation of the -carbon or the aromatic ring decreases  CNS
activity due to  ability to cross BBB.
 Halogenations (F, Cl, Br) of the aromatic ring  central nervous system
activity and ↑ anorectic activity, e.g., 4-chloroamphetamine.
6
 There is a high structure similarity between amphetamines and NE/E.
This similarity enables them to have complex and multiple actions in the
synthesis of NE, its release and uptake. Also, dopamine and serotonin
(5-HT) activated systems could be involved due to structure resemblance
to NE.
Amphetamine (Dexamphetamine, Dextroamphetamine)
S(+) -Methyl--phenethylamine (S>R)
(S(+) 1-Phenyl-2-aminopropane).
 Amphetamine causes ↑↑ dopamine release resulting in acute psychosis of
paranoid nature.
 The -methyl group retards but does not terminate metabolism by MAO.
 It is metabolized by N-dealkylation to phenylacetone and ammonia.
Phenylacetone is further metabolized to benzoic, then to hippuric acid.
7
Metabolism of Amphetamine:
Urinary metabolites of amphetamine in humans.
Methamphetamine
H
N
CH3
CH3
(+) N-Dimethyl--phenethylamine
 It is the N-methyl analogue of dextroamphetamine.
 It has more central activity i.e., ↑ activity as CNS stimulant, and more
abuse potential.
 Thus, amphetamine and methamphetamine have CNS stimulant action
more than anorectic action.
8
 Modifications done to ↑ anorectic activity resulted in:
Benzamphetamine
N-Benzyl-N,-dimethylphenethylamine
The NH2 group of amphetamines was substituted with a bulky group
rather than CH3 group, i.e., a benzyl group (↑ Anorectic > CNS stimulation).
Fenfluramine (Ponderex)
 Where substitution on the phenyl ring with a halide  anorectic activity
> CNS stimulation.
 It is used in weight reduction in non-insulin diabetic patients.
Sibutramine (Reductil, Merida)
9
It is an agent with an amphetamine-like structural skeleton that was
initially developed as an antidepressant. It inhibits serotonin and NE reuptake.
Then animal studies indicated that it reduces the amount of visceral fat. It is used
to reduce weight but it has side effects that include ↑ heart rate and blood
pressure due to its adrenergic action.
2-
Central Sympathomimetics Containing (N) in Cyclic
Structure
Benzyl Derivatives
Methylphenidate (Ritalin)
-Phenyl-2-piperidine acetic acid methyl ester or methyl -phenyl--2piperidylacetate
 It has two chiral centres and four possible isomers. The threo-racemate is
about 400 times as potent as erythro-racemate and is the marketed
compound.
 It is a potent CNS stimulant, indicated in cases of narcolepsy and attention
deficiency disorders.
10
 Metabolism of Ritalin
a.
(80-90%): is hydrolyzed after absorption from stomach into ritalinic
acid (inactive).
b.
(5%): by hepatic microsomal enzymes ⇒ cyclic amides (inactive).
c.
(4%): in brain: p-hydroxylation on the phenyl ring ⇒ (active).
11
III- Methylxanthines
Caffeine, theophylline and theobromine are the members of this group
(natural alkaloids), which differ in potency and the relative pharmacological
properties of the xanthenes are shown in the following table:
Central Nervous
System, Respiratory,
and Skeletal Muscle
Stimulation
Cardiac, Stimulation,
Coronary Dilatation, Smooth
Muscle Relaxation, Diuresis,
and Goitrogenic Potential
Caffeine
1
3
Theophylline
2
1
Theobromine
3
2
Structure
Mode of Action:
The CNS stimulant action is related to the ability of these compounds to
act as competitive inhibitors at certain receptors stimulated by adenosine.
(Adenosine, is present in mast cells, exerts pronounced cardiac, vascular,
metabolic and gastrointestinal effect).
Uses
 Caffeine is used in treatment of migraine and headaches.
12
 While theophylline and theobromine are used mainly in the treatment of
asthma because of their bronchiodilating properties.
Pentoxifylline (Trental)
3,7-Dimethyl-1-(5-oxohexyl)xanthine

Pentoxifylline, a synthetic methylxanthine is used for:
1. Treatment of peripheral vascular diseases.
2. Improve red blood cells deformability, permitting more effective
blood flow through occluded pathways.
3.  blood viscosity.
13
IV- Antidepressants
Depression

It is a disorder or disease characterized by irritability, impaired
judgement, despair, anorexia, sadness and sometimes suicidal behaviour.

It occurs due to:
1. Deficiency in biogenic amines (Endogenous) e.g., NE, 5-HT,
tryptamine and tyramine.
2. Shock ⇒ depression (Exogenous).

Classes of Antidepressants:
1. Monoamine Oxidase Inhibitors (MAOI)
2. Tricyclic Antidepressants (TCA)
1.
Monoamine Oxidase Inhibitors (MAOI)

MAO is a family of flavin containing enzymes located primarily in the
membranes of mitochondria. These enzymes inactivate  biogenic
amines as NE, serotonin (5-HT) tryptamine and tyramine by conversion
of these amines to aldehydes which are subsequently oxidized to acid or
reduced to alcohol.

MAO enzymes are subdivided into:
 MAO-A for NE, 5-HT (low).
 MAO-B for dopamine (high).
14
 MAOI inhibit these receptors ⇒ ↑↑ Epinephrine, Norepinephrine and
Serotonin.

Uses of MAOI:
 It is used for treatment of major depressive disorders besides
electric shock therapy (suicidal patients).

Side Effects of MAOI:
 Severe
hypertensive
responses
especially
if
taken
with
sympathomimetic drugs or taken with tyramine.
 Severe, sometimes fatal hypertension following ingestion of
foods high in pressor amines. So, MAOI must be taken under
medical supervision and only in severe cases.
First-Generation MAOI; Irreversible, Nonselective
Tranylcypromine Sulphate (Parnate)
() Trans-2-phenylcyclopropylamine
 As tranylcypromine is considered the cyclic form of amphetamine, so it
has some amphetamine-like properties.
15
 It is a mechanism-based inactivator where it reacts covalently (forms an
irreversible covalent bond) with the enzyme resulting in MAO
inactivation.
 It is a potent CNS stimulant and is the most dangerous ⇒ hypertensive
crisis.
Pargyline (Eutonyl)
N-Methyl-N-2-propynylbenzylamine
Pargyline is usually used for its hypotensive properties because although
it is an active MAOI, yet it is believed that the accumulated tyramine, as a result
of MAO inhibition is converted by -hydroxylation to octopamine ,which is
stored and it acts as a false neurotransmitter with a weaker pressor activity than
NE which it replaces.
16
Second-Generation MAOI, Irreversible, Preferential
Deprenyl/Selegiline
N-Methyl-N-2-propynyl--methylphenethylamine
 Deprenyl is a preferentially MAO-B inhibitor, so it has the advantage of
sparing liver MAO-A and thereby avoiding the “Cheese Effect” or the
hypertensive response to tyramine and other dietary pressor amines.
 It is used in treatment of Parkinsonism as it ↑↑ dopamine level in the
brain.
Third-Generation MAOI; Reversible, Preferential or
Reversible Inhibitors of MAO (RIMA)
Meclobemide
4-Fluoro-N-[2-(N-morpholino)ethyl]benzamide
It differs from the previous MAOI in that:
 It is selective MAO-A inhibitor.
 It is reversible which binds to the enzyme by H-bond (not covalent).
17
 It causes less hypertensive crisis.
2-
Tricyclic Antidepressants (TCA)

Almost all TCA block neuronal uptake of NE, 5-HT and dopamine (DA).

Some agents block the uptake of transmitters and others are not involved
in this property. Yet, all blockers share the property of ↑ increasing NE,
5-HT and DA.

Mode of Action:
Blocking neuronal uptake of NE and 5-HT.

Advantages:
More safe than MAOI, so can be used with no diet control and used for
children in bed wetting.

Structure-Activity Relationships (SAR)
 The structure of TCA comprises a large group encompassing two
aromatic rings, preferably held in a skewed arrangement by a third
central ring (lacking coplanarity).
 If the central aromatic ring is a 6-membered ring ⇒ phenothiazines
antipsychotics (tranquillizers).
18
But if it is a 7-membered ring (similar to NE and 5-HT when they bind to
the receptor) ⇒ antidepressants.
 To the central ring-a three or sometimes two carbon chain-attached to
an aliphatic amino group (e.g., monoethyl- or dimethyl-substituted) is
a must. These features could be visualized in the structures of
imipramine and desimpramine as examples.
 Many of the antidepressant drugs have close structural similarity to
DA blockers (antipsychotics) and NE blockers (sedatives). In fact,
many antidepressants retain appreciable antipsychotic and sedative
properties.
Imipramine (Tofranil)
N
CH3
 HCl
CH3
5-[3-(Dimethylamino)propyl]-10,11-dihydro-5-H-dibenzo[b,f]azepine HCl
 It is the parent compound of TCA.
 It is close relative to the antipsychotic phenothiazines (isosteric
replacement of 10-11 bridge with sulpher).
19
Metabolism:
 Metabolic N-demethylation gives nor- or (des-) imipramine which is
more active than the parent imipramine.
 Imipramine has longer duration of action due to its metabolism to the
active metabolite.
Synthesis of Imipramine
Reduction
NO2 NO2
NH2 NH2
280NC
- NH3
CH3
N
CH3
Cl
N
H
Imipramine
- HCl
Desipramine (Norpramine)
5-(3-Methylaminopropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine HCl
20
Clomipramine (Anafranil)
5-[3-(Dimethylamino)propyl]-3-chloro-10,11-dihydro-dibenzo[b,f]azepine HCl
It is a potent antidepressant due to the chloro-substitution at the
3-position which ↑ lipophilicity.
Amitriptyline (Elavil, Triptizol)
3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1propanamine HCl.
 It is one of the most sedatives of TCA with the most anticholinergic
activity.
 Metabolic N-demethylation occurs to give nortryptyline which has 
sedative and  anticholinergic action than amitriptyline.
21
Doxepin (Sinequan)
 The oxygen placed is the isostere of –CH2- .
 The oxygen introduces asymmetry into the tricyclic ring system resulting
in the formation of 2 geometric isomers: E (trans) and Z (cis).
 The Z (cis) isomer is more active than E (trans) isomer.
Maprotiline (Ludiomil)
It is a tetracyclic compound with has stimulant activity with 
anticholinergic properties (due to 2 ary amine). In other words, its main action is
on NE not 5-HT).
22
Trazodone (Desyrel)
 Trazodone is a phenylpiperazine-triazolopyridine antidepressant that is
not structurally related to most of the other antidepressants.
 It inhibits (blocks) presynaptic uptake of 5-HT ⇒ ↑ sedation.
Fluoxetine (Prozac)
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). In other
words, it is a potent and selective inhibitor of 5-HT reuptake, but not of NE or DA
uptake in the CNS.
23