P R E S E N T E D B Y

DR. GHADA SAMEH HAFEZHASSAN

CNS STIMULANTS

DR. GHADA SAMEH HAFEZHASSAN

GHADASAMEH@MANS.EDU.EG

Central Nervous System Stimulants

Drugs that produce stimulation of the central nervous system

could be classified into the following categories:

Analeptics: as respiratory stimulants EX. Methylxanthines

Central sympathominetics: Amphetamine and closed relatives,

have altering and antidepressant properties, but are now usedhave altering and antidepressant properties, but are now used

as anorexients.

Antidepressants drugs: the monoamine oxidase inhibitors

(MAOI) and the tricyclic, mechanistically related drugs.

Psychedelic drugs: these drugs have broad range of CNS effects

including CNS stimulation.

1- ANALEPTICS

Analeptics

The analeptics are a group of potent and relatively

nonselective CNS stimulants and their convulsive dose lies

near their analeptic dose.near their analeptic dose.

They had previously employed as respiratory stimulants,

however they are now obsolete for that use.

Analeptics

N

OO

H

NH

HO

OO H

OO

OH

CH3

Picrotoxinin

N NN

N

Pentylenetetrazole

Strychnine, picrotoxin and pentylenetetrazole have usefulness as pharmacologictools and have interesting mechanisms ofaction??????

OOStrychnine HH2C

Niketamide (Coramine)

N

CON(C2H5)2

Niketamide

Niketamide stimulates respiration withoutinducing generalized CNS stimulation. Thedrug is obsolete in managing poisoning forsedative-hypontic drugs.

Modafinil (Provigil)

It is considered as a typical1-norepinephrinereceptor stimulant and isused to treat daytime

SH

NH2

O

O

used to treat daytimesleeping in narcolepsypatients.

H O

Modafinil

Methylxanthines

N

N N

N

O

H3CO

CH3

CH3

Caffeine

N

N N

N

O

H3CO

CH3

H

Theophylline

N

N N

N

O

HO

CH3

CH3

Theobromine

The CNS stimulant action is related to the ability ofthese compounds to antagonize adenosine Areceptors.

These compounds are usually dispensed in avariety of mixtures or complexes to increasesolubility in water as citrated caffeine, caffeinesodium benzoate, theophyline ethylenediamine(Aminophylline).

Caffeine

2-Central SympothomimeticAgents (Psychomotor

Stimulants)

Central Sympothomimetic Agents

The group of indirect sympathetic agonist where obtained by

certain structure modification of NE that lead to production

of compounds more resistant to metabolism and better able

to cross the blood-brain barrier.

These effects increase the proportion of central to peripheral These effects increase the proportion of central to peripheral

activity and sometimes referred as central sympathomimetic

agents.

There central activity is manifested as excitation,

wakefulness, in addition to anorexient effects. Dopaminergic

and serotoninergic effects are also operative.

Central Sympothomimetic Agents

H2C

H2C NH2

meta

para

phenylethylamine

They are -phenethylamine derivatives.Amphetamine is the prototype of this group.

-phenethylamine is without central activitydue to facile metabolic inactivation by MAO.

phenylethylamine

Structure Activity Relationship

Branching with lower alkyl groups on the -carbon increases CNS rather than peripheralactivity, presumably by retarding metabolism.

The -branching generates chiral center andstereoselectivity of possible enantiomers isThe -branching generates chiral center andstereoselectivity of possible enantiomers isapparent.

Hydroxylation of the -carbon or the aromaticring decreases activity, as the result ofdecreasing ability to cross the blood-brainbarrier.

Amphetamine Sulfate (Benzedrine)

The racemic mixture has a higher properties of

CH3

NH2

*

Amphetamine

The racemic mixture has a higher properties ofcardiovascular effects than the dextro-isomer. For mostmedical uses, the dextro-isomer is preferred.

The -methyl group retards but not terminates, metabolismby MAO. It is metabolized by N-dealkylation to phenylacetoneand ammonia. Phenylacetone is further metabolized tobenzoic acid.

CH3

NH2

Amphetamine

CH3

NH2

CH3

NH2

CH3

O

P-Hydroxyamphetamine Norephedrine PhenylacetoneHO

OH

COOH

Benzoic acid

CH3

NH2

P-Hydroxynorephedrine

HO

OH

NH

COOH

O

Hippuric acid

Urinary metabolites of amphetamine in humans.

Methamphetamine hydrochloride

HN

CH3

CH3

Methamphetamine

Methamphetamine is the N-methylanalogue of dextroanphetamine.

It has more central activity and more abuse potential.

Methamphetamine

Chlorphentermine hydrochloride

NH2

CH3

CH3

Cl

Chlorphentermine is an effective anorexient with less abuse potential than dextroamphetamine

Methylphenidate Hydrochloride

HN OCH3

O

**

HCl

Methylphenidate has two chiral centers and have four possible isomers.

The threo-racemate is about 400 times as potent as erythro –racemate and it is the marketed compound.

O

Methylphenidate HCl

Methylphenidate Hydrochloride

CH2CN

+

HNCl

NaNH2CH

HN

CN

CHHN

COOH

Hydrolysis

Esterification

CH3OH/H2SO4

Drug

TricyclicAntidepressants (TCA)

Tricyclic Antidepressants (TCA)

Almost all TCA block neuronal uptake of NE, 5-

HT and DA.

Some agents block the uptake of the transmitters

and other are not involved in this property.

Yet, all blockers share the property of increasing

synaptic availability of NE, 5-HTand DA.

Tricyclic Antidepressants (TCA)

The structure of TCA comprised a large bulkygroup encompassing two aromatic rings,preferably held in a skewed arrangement by athird central ring.

This tricyclic bulky structure lacks coplanirity.

To the central ring a three or sometimes two-atom chain attached to an aliphatic amino groupthat is monoethyl- or dimethyl-substituted.

Imipramine Hydrochloride (Tofranil)

N

N(CH3)2

1

2

34

5

67

8

910 11

Imipramine

It is the parent compound of TCA.

Metabolic deactivation proceeds mainly by oxidativehydroxylation in the 2-position followed by conjugation.

Metabolic N-demethylation gives nor- (or des-) imipramine

The demethylated metabolite is less cholinergic and lesssedative, more stimulatory and higher NE than 5-HT uptake-blocking capability.

Imipramine Hydrochloride (Tofranil)

O2NNO2 H2NNH2

Red.

H2/Pd

280 oC

N

H

Drug

H3C

H3C

H2C

H2C Cl+

-HCl

Clomipramine

N

N(CH3)2

1

2

3

4

5

67

8

910 11

Cl

Clomipramine has structure parallism with the

antipsychotics (e.g. chlorophromazine).

It is a strongly sedative and very strong 5-HT up take

blocker. Its N-demethyl metabolite is reported to be

both a 5-HT and Ne uptake blocker.

N(CH3)2Clomipramine

Amitriptyline Hydrochloride (Elavil]

N(CH3)2

1

2

3

45

67

8

910 11

Amitriptyline

a

b c

d

Since it lacks ring electron-enriching nitrogenatom of imipramine, metabolic inactivation mainlyproceeds via benzylic oxidation at position 10- andnot 2-position (toluene like metabolism).

Metabolic N-demethylation occurs to givenortriptyline which has a less anticholinergic, lesssedative and more stimulant action thanamitriphyline.

Doxepin Hydrochloride (Sinequan)

O

N(CH3)2

12

3

4

567

8

910

11

Doxepin

a

dcd

e

The oxygen placed is isostere of the –CH2- and wellas post- and presynaptic binding affinities.

The drug is a NE and 5-HT uptake blocker withsignificant anticholinergic and sedative properties.

Doxepin

Doxepin Hydrochloride (Sinequan)

CH2Br

CN

+

ONa

-NaBr

CN

O

Hydrolysis

COOH

O

(CF3COO)2O3 2

Cyclization

O

O

H3C

H3C(CH2)3MgCl

O

(CH2)3N(CH3)2HO

Drug-H2O