P R E S E N T E D B Y
DR. GHADA SAMEH HAFEZHASSAN
CNS STIMULANTS
DR. GHADA SAMEH HAFEZHASSAN
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 Thedrug is obsolete in managing poisoning forsedative-hypontic drugs.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