Download CNS STIMULANTS

CNS STIMULANTS
PRESENTED BY
DR. GHADA SAMEH HAFEZ
HASSAN
[email protected]
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 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.
 They had previously employed as respiratory stimulants,
however they are now obsolete for that use.
Analeptics
H
O
N
O
H
H
N
O
O
 Strychnine,
H2C
N
CH3
O
O
OH
Picrotoxinin
O
Strychnine
H
N
N
N
Pentylenetetrazole
H
picrotoxin
and
pentylene
tetrazole have usefulness as pharmacologic
tools and have interesting mechanisms of
action??????
Niketamide (Coramine)
CON(C 2H5) 2
N
Niketamide
 Niketamide stimulates respiration without
inducing generalized CNS stimulation. The
drug is obsolete in managing poisoning for
sedative-hypontic drugs.
Modafinil (Provigil)
 It is considered as a typical
1-norepinephrine
receptor stimulant and is
used to treat daytime
sleeping in narcolepsy
patients.
O
NH2
S
H
O
Modafinil
Methylxanthines
O
H 3C
O
N
CH 3
N
N
N
CH3
Caffeine
O
H3C
O
N
O
H
N
H
N
N
CH3
O
Theophylline
N
CH 3
N
N
N
CH3
Theobromine
 The CNS stimulant action is related to the ability of
these compounds to antagonize adenosine A
receptors.
 These compounds are usually dispensed in a
variety of mixtures or complexes to increase
solubility in water as citrated caffeine, caffeine
sodium benzoate, theophyline ethylenediamine
(Aminophylline).
2-Central Sympothomimetic
Agents (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
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
meta
para
H2
C
H2
C


NH2
phenylethylamine
are -phenethylamine derivatives.
Amphetamine is the prototype of this group.
 They
 -phenethylamine is without central activity
due to facile metabolic inactivation by MAO.
Structure Activity Relationship
 Branching with lower alkyl groups on the -
carbon increases CNS rather than peripheral
activity, presumably by retarding metabolism.
 The -branching generates chiral center and
stereoselectivity
apparent.
of
possible
enantiomers
is
 Hydroxylation of the -carbon or the aromatic
ring decreases activity, as the result of
decreasing ability to cross the blood-brain
barrier.
Amphetamine Sulfate (Benzedrine)
*
CH 3
NH2
Amphetamine
 The
racemic mixture has a higher properties of
cardiovascular effects than the dextro-isomer. For most
medical uses, the dextro-isomer is preferred.
 The -methyl group retards but not terminates, metabolism
by MAO. It is metabolized by N-dealkylation to phenylacetone
and ammonia. Phenylacetone is further metabolized to
benzoic acid.
CH3
NH2
Amphetamine
OH
CH3
CH3
NH2
NH2
HO
P-Hydroxyamphetamine
CH3
Norephedrine
O
Phenylacetone
OH
COOH
CH3
HO
NH2
P-Hydroxynorephedrine
O
Benzoic acid
N
H
COOH
Hippuric acid
Urinary metabolites of amphetamine in humans.
Methamphetamine hydrochloride
H
N
CH3
CH3
Methamphetamine
 Methamphetamine is the N-methylanalogue of dextroanphetamine.
 It has more central activity and more abuse potential.
Chlorphentermine hydrochloride
CH 3
Cl
NH 2
CH 3
 Chlorphentermine is an effective anorexient with less
abuse potential than dextroamphetamine
Methylphenidate Hydrochloride
H
N
HCl
*
OCH 3
*
O
Methylphenidate 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.
Methylphenidate Hydrochloride
CH2CN Cl
H
N
CN
NaNH2
CH
H
N
+
Hydrolysis
COOH
Drug
Esterification
CH3OH/H2SO4
CH
H
N
Tricyclic
Antidepressants (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 bulky
group encompassing two aromatic rings,
preferably held in a skewed arrangement by a
third central ring.
 This tricyclic bulky structure lacks coplanirity.
 To the central ring a three or sometimes two-
atom chain attached to an aliphatic amino group
that is monoethyl- or dimethyl-substituted.
Imipramine Hydrochloride (Tofranil)
10
11
9
1
2
8
5
7
N
6
Imipramine
3
4
N(CH 3) 2
 It is the parent compound of TCA.
 Metabolic
deactivation
proceeds
mainly
by
oxidative
hydroxylation in the 2-position followed by conjugation.
 Metabolic N-demethylation gives nor- (or des-) imipramine
 The
demethylated metabolite is less cholinergic and less
sedative, more stimulatory and higher NE than 5-HT uptakeblocking capability.
Imipramine Hydrochloride (Tofranil)
Red.
H2/Pd
NO2 O2N
NH2 H2N
280 oC
+
Drug
H3C
H2 H2
C C Cl
H3C
-HCl
N
H
Clomipramine
10
11
9
1
8
2
5
7
N
6
3
Cl
4
N(CH3 )2
Clomipramine
 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.
Amitriptyline Hydrochloride (Elavil]
10
11
9
1
8
2
d
a
b c
7
6
5
3
4
Amitriptyline
N(CH3 )2
 Since it lacks ring electron-enriching nitrogen
atom of imipramine, metabolic inactivation mainly
proceeds via benzylic oxidation at position 10- and
not 2-position (toluene like metabolism).
 Metabolic
N-demethylation
occurs
to
give
nortriptyline which has a less anticholinergic, less
sedative and more stimulant action than
amitriphyline.
Doxepin Hydrochloride (Sinequan)
5
6
7
O
4
a
8
e
3
d
d c
9
10
11
1
Doxepin
2
N(CH3 )2
 The oxygen placed is isostere of the –CH2- and well
as post- and presynaptic binding affinities.
 The drug is a NE and 5-HT uptake blocker with
significant anticholinergic and sedative properties.
Doxepin Hydrochloride (Sinequan)
CH2 Br
O
ONa
Hydrolysis
-NaBr
+
O
CN
CN
COOH
(CF3 COO)2 O
Cyclization
O
Drug
-H 2 O
H3 C
H3 C
HO
(CH2 )3 N(CH3 )2
O
(CH2 )3 MgCl
O