Download Drugs Acting on CNS

Drugs Acting on CNS
CNS Depressants
Antiepileptic Agents
INTRODUCTION

Epilepsy is one of the most common disorders
of the brain, affecting about 50 million
individuals worldwide. Epilepsy is a chronic and
often progressive disorder characterized by the
periodic and unpredictable occurrence of
epileptic seizures that are caused by abnormal
discharge of cerebral neurons. Epilepsy is not a
disease, but a syndrome of different cerebral
disorders of the CNS.
INTRODUCTION

This syndrome is characterized by paroxysmal,
excessive, and hypersynchronous discharges of
large numbers of neurons. These seizures may
be identified on the basis of their clinical
characteristics. These clinical attributes, along
with their electroencephalographic (EEG)
pattern, can be used to categorize seizures.
INTRODUCTION
Seizures are basically divided into two major
groups:
 Partial (focal, local) seizures are those in which
clinical or EEG evidence exists to indicate that
the disorder originates from a localized origin,
usually in a portion of one hemisphere in the
brain.
 Generalized seizures, the evidence for a local
origin is lacking.

INTRODUCTION


The goal of therapy with an anticonvulsant agent is to
have the patient seizure free without interfering with
normal brain function. Thus, the selection of an
anticonvulsant agent is based primarily on its efficacy
for specific types of seizures and epilepsy.
They are used for the prevention of different types of
epileptic seizures. They act through decreasing the
electrical excitability at the site of epilepsy or at
adjacent neurons.
INTRODUCTION

They are used for the prevention of different
types of epileptic seizures. They act through
decreasing the electrical excitability at the site
of epilepsy or at adjacent neurons.

Several classes of compounds belonging to
different nuclei are used,
1. Barbiturates
(Barbituric acid derivatives)
Al
barbiturates
barbiturc acid.
are
derivatives
of
Depending on:
The drug structure
The dose
The route of administration
The drug can produce different CNS
depression such as sedative, hypnotic,
anticonvulsant or anesthetic.
They
are widely used until the discovery
of benzodiazepines???
MECHANISM OF ACTION
γ-Aminobutyric
acid (GABA) represents
the most important inhibitory transmitter
of the mammalian CNS, it act through
regulation of chloride channel of neuronal
membrane.
Barbiturates
act
postsynaptically
to
promote GABA binding → prolong the
mean open time of chloride channel →
CNS depressant effect.
BARBITURIC ACID
O
4 NH
3
5
6 1 2
O
N
O
H
2,4,6-Trioxohexahydropyrimidine
It has no CNS depressant activity
Barbiturates
• All
barbiturates
are
5,5disubstituted barbituric acid.
• Some are with substitution at
N1
O
R1
R
2
O
5
6
4
3NH
1 2
N
H
O

CHARACTERS
1.
They are acid,
enolate salt.
dissolve
O
R
O
R1
NH
R
NH
2
R
N
H
NaOH
O
1
2
in
O
O
O
NaOH
R1
NH
2
R
O
N
N
O Na
OH
→
CHARACTERS
2.
They decompose by heating with strong
alkali with the formation of ammonia and
disubstituted acetic acid.
O
1
R
R
O
R1
NH
2
N
H
O
O
C ONa
4 NaOH
2
R
C
C ONa
O
R1
CH C ONa
R2
O
+ 2 NH3 + Na2CO3
CHARACTERS
3.
They are classified according to the
duration of action into
1)
Long acting barbiturates
2)
intermediate acting barbiturates
3)
Short acting barbiturates
4)
Ultra short acting barbiturates
Long acting barbiturates
Duration: 6 hours or more
Onset: 30-60 minutes
O
O
C52H5 O O
C2H
C2H
R51
NH
NH
NHNH
C2H
R52
O NN
O
OO
O
NN O O
O
HCH
HR
3 3
Phenobarbital
Barbital
Mephobarbital
5-Ethyl-5-phenylbarbituric
acid acid
5,5-diethylbarbituric acid
5-Ethyl-5-phenyl-1-methylbarbituric
Generic/Trade name
R1
R2
R3
1- Barbital (Veronal®)
Ethyl
Ethyl
H
2-Phenobarbital
(Luminal®)
Ethyl
Phenyl
H
3-Mephobarbital
(Meboral®)
Ethyl
Phenyl
CH3
Intermediate acting
barbiturates
Duration: 3-6 hours
Onset: 20-30 minutes
CH3 CH3 O
O
H3HC3C 1 O
H3C
R
NH
NH
C
H
NH
H2C C22H
2 55
R
O
N
O
O
N
O
O
N
O
H
H
CH
Amobarbital
H
CH
Butabarbital
Aprobarbital
CH
5-Ethyl-5-isopentylbarbituric
acid acid
5-Ethyl-5-(1-methylpropyl)barbituric
5-Allyl-5-isoproylbarbituric acid
3
3
Generic/Trade
name
1- Amobarbital
(Amytol®)
2-Butabarbital
(Butisol®)
3-Aprobarbital
(Alurate®)
R1
Ethyl
Ethyl
-CH2CH=CH2
R2
H2 H2 CH3
C C CH
CH3
H H2
C C CH3
CH3
Short acting
barbiturates
Duration: 1-3 hours
Onset: 10-15 minutes
CH33 O
CH
O
OO
R1
NH
NH
NH
C22H5 NH
H5
HC
2R
2C
O
N
O
O
N
O
OO NN OO
H
H
HH
Pentobarbital
Secobarbital
Cyclobarbital
5-Ethyl-5-(1-methylbutyl)barbituric
acid
5-Allyl-5-(1-methylbutyl)barbituric acid
5-(1-Cyclohexenyl)-5-ethylbarbituric acid
Generic/Trade
R1
R2
name
H H2 H2
1- Pentobarbital
C C C CH3
Ethyl
CH3
(Nembutal®)
2- Secobarbital
H H2 H2
C C C CH3
-CH2CH=CH2
®
(Seconal )
CH3
3-Cyclobarbital
Ethyl
(Phandoran®)
H33C
C
H
Ultra short acting
barbiturates
Duration: 10-30 minutes
Onset: few seconds after IV
THIOPENTOBARBITAL,
THIOPENTAL SODIUM
(PENTOTHAL SOD.®)
CH3 O
H3C
NH
C2H5
O
N
SNa
Thiopentobarbital, Thiopental sodium
5-Ethyl-5-(1-methylbutyl)-2-thiobarbituric
acid sodium salt
THIOSECOOBARBITAL,
THIAMYLAL SODIUM
(SURITAL SOD.®)
CH3 O
H3C
NH
O
N
SNa
Thiosecoobarbital, Thiamylal sodium
5-Allyl-5-(1-methylbutyl)-2-thiobarbituric
acid sodium salt
GENERAL METHOD FOR PREARATION
OF 5,5-DIALKYLBARBITURATES
O
O
OEt
NaOEt
R1
H2C
OEt
C
OEt
H
R1X
O
Na
OE
t
OEt
O
R2
X
O
R1
R2
O
O
R1
NH
R2
O
N
H
NH2
NH2
C
H
R1
NH
R2
O
N
O
ONa
OE
a
N
OEt
C
OEt
O
t

Substitution of urea with thiourea
→
2-Thiobarbiturates.

In
case
of
N1-substitution
we
use
NHR3CONH2.

It is difficult to introduce aryl group into
diethyl malonate by alkylation so, in case
of phenobarbital we use the following
method:-
PREARATION OF PHENOBARBITAL
CN
Cl
KCN
COOEt
EtOH
H
NaOEt
COOEt
H COOEt
O
H
C OEt
Distillation
C OEt
COOEt
C COOEt
O
- CO2
Et I
NaOEt
O
Et
O
C OEt
C OEt
O
NH2
O C
NH2
NaOEt
O
H
N
O
Et
NH
O
Phenobarbital
STRUCTURE ACTIVITY RELATIONSHIP
(SAR)
1.
Both hydrogen atoms at C5 of barbituric acid
must be substituted giving 5,5-disubstituted
barbituric acid. Why??
a)
A-if only one hydrogen is substituted →
toutomerization of the molecule to a
highly
acidic
trihydroxypyrimidine
derivatives
with
lower
lipophilic
characters
O
O
R
R
NH
H
O
OH
N
H
O
R
NH
H
O
OH
N
OH
H
O
R
N
N
N
OH
HO
N
OH
STRUCTURE ACTIVITY RELATIONSHIP
(SAR)
b)
In addition this position(C5) is highly
susceptible to rapid metabolic attack.
2.
↑ length of the alkyl chain at C5 → ↑ lipophilic
characters
→
↑ability
of
the
drug
to
penetrate BBB and → ↑ potency of the drug,
up to 5-6 C-atom (as hydrophilic characters
are important for the solubility in biological
fluids )
STRUCTURE ACTIVITY RELATIONSHIP
(SAR)
3.
Branching, unsaturation, replacement of
alicyclic substituents for alkyl substituents
→↑lipid solubility → ↓ duration of action (due
to increasing the rate of
metabolic
conversion to inactive metabolite )
4.
Substitution of one nitrogen with short alkyl
group (ethyl or propyl) → ↑ lipophilic
characters and enhance the anticonvulsant
activity.
But substitution at both nitrogen → non acidic,
inactive drugs
STRUCTURE ACTIVITY RELATIONSHIP
(SAR)
5.
Phenyl group at position-5 enhances the
anticonvulsant activity and prolong duration.
6.
Introduction of polar group at position-5 →
destroy the CNS depressant activity.
7.
Isosteric replacement of O-atom by S-atom
at position-2→ Thiobarbiturates with ultra
short acting

Phenobarbitone and mephobarbitone are the
most commonly used barbiturates as
anticonvulsants
2- Hydantoins
INTRODUCTION
They are cyclic monoacylureas
 They
are weaker organic acids than
barbiturates.
 All clinically effective drugs with an aryl
substitution at 5-position.

R
R
R
O
NH
5 1
4
2
3
N
R
N
R
O
O
N
R
OH
1- DIPHENYL HYDANTOIN (EPANUTIN,
PHENYTOIN)

It is one of the most effective and widely used
epileptics
Ph
Ph
O
NH
N
Na
O
5,5-Diphenylhydantoin sodium
SYNTHESIS
Ph
NH 2
Ph
O
Ph
Br
N
Na
O
Alc. NH3
Ph
O
NH
N
Na
O
2- ETHOTOIN (PEGANONE)
Ph
NH
O
N
O
C2H 5
3-Ethyl-5-phenylhydantoin
3- Oxazolidindiones
1- TRIMETHADIONE (TRIDIONE)
CH3
H3C
O
5
4
Synthesis
O1
3 2
N
O
H 3C
CH3
3,5,5-Trimethyl-2,4-oxazolidine
C O
N
CH3
OH
C
CN
H3C
H3C
1-Hydrolysis
2-Esterification
CH3
O
H 3C
O
H 3C
KCN
O
H3C
(C
Na
O
H
3)
2
SO
4
H
CH3
O
H 3C
O
N
H
O
H 2N
O
H 3C
NH2
Et
O
Na
OH
C
COOEt
2- PARAMETHADIONE (PARADIONE)
C2H 5
O
H 3C
O
N
O
CH 3
5-Ethyl-3,5-drimethyl-2,4-oxazolidine
4- Succinimides
1- PHENSUXIMIDE
Ph
O
N
O
CH 3
N-Methyl-2-phenylsuccinimide
Metabolized by N-demethylation → Ndemethylated (Active metabolite)
 Phensuximide and its active metabolite are
inactivated via p-hydroxylation.

2- METHSUXIMIDE AND ETHOSUXIMIDE
C2H5
H3C
H3C
Ph
O
N
O
CH3
N,2-Dimethyl-2-phenylsuccinimide
O
2
1
N
3
4
O
H
2-Ethyl-2-methylsuccinimide
5-Benzodiazepines
They
are the drugs of choice for treatment of
anxiety.
They are used as
sedative-hypnotics
 Muscle relaxant
Anticonvulsant
They are characterized by:Higher activity.
Wide therapeutic range (Safe).
No respiratory depression as
barbiturate
in case of
MECHANISM OF ACTION



They
bind
and
stimulate
specific
benzodiazepine receptors (BZ1 & BZ2) which
are adjacent to GABAA receptors.
These GABAA receptors are involved in the
regulation of the chloride channel.
As a result, they increase the binding of
GABA with GABAA receptors and so the
intensity of the action of GABA resulting in
opening of chloride channel and the influx of
Cl- ions into neuron leading to neuronal
inhibition.
1-CHLORODIAZEPOXDE (LIBRIUM®)
9
8
1
N
NHCH3
3
7
Cl
2
6
5
N4
O
7-Chloro-2-methylamino-5-phenyl-3H1,4-benzodiazepin-4-oxide
DISCOVERY
It was prepared by chance. How??
During
the
synthesis
of
6-chloro-2-
methylaminomethyl-4-phenylquinazolin-3oxide where the ring expansion occur →
Chlorodiazepoxde
N
Cl
H
N
NHCH3
N
O
N2HCH3
NHCH3
N
Cl
C
Cl
H2
O
H
N2HCH3
N
Cl
CH2NHCH3
N
O
NHCH3
N
Cl
N
O
METABOLISM
NHCH3
N
N
Cl
H
N
O
O
Re
du
Nordiazepam
Oxidative
deamination
cti
on
Cl
Hydroxylation
H
N
Cl
O
N
O
NHCH3
N
OH
Cl
Oxazepam
io
n
N
NH2
N
N
Cl
Nde
alk
yla
t
Demoxepam
(Major metabolite)
Conjugated and excreted
N
O
2- DIAZEPAM (VALIUM®)
CH3
9
8
1
N
O
3
7
Cl
2
6
5
N4
7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H1,4-benzodiazepin-2-one


Used mainly as anxiolytic, sedativehypnotic,
muscle
relaxant
and
anticonvulsant.
It is one of the most widely used
benzodiazepin.
METABOLISM
CH3
O
N
N
Cl
e
N-D
H
N
alk
ti
yla
O
Hy
dr
ox
yla
tio
on
n
Diazepam
CH3
O
N
OH
Cl
N
Hy
Nordiazepam
dr
ox
y la
t io
Cl
n
Cl
n
tio
a
l
ky
l
O
a
e
N-D
OH
H
N
N
Oxazepam
N
Temazepam
3- OXAZEPAM (SERAX®)
H
N
O
OH
Cl
N
7-Chloro-1,3-dihydro-3-hydroxyl-5-phenyl2H-1,4-benzodiazepin-2-one

The prototype for 3-hydroxy compounds.

It Possesses short duration of action.
4- LORAZEPAM (ATIVAN®)
H
N
O
OH
Cl
N
Cl
7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxyl2H-1,4-benzodiazepin-2-one

The presence of 2-chloro substitution → ↑
increase CNS depressant activity
5- CLORAZEPATE DIPOTASSIUM
(TRANXENE®)
H
N
O
COO K
Cl
KOH
N
7-Chloro-1,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepin
-3-carboxylic acid dipotassium salt monohydrate
It
is a prodrug. In vivo it is decarboxylate
→nordiazepam, which has a long-half life and
undergoes hepatic conversion to oxazepam.
6- ALPRAZOLAM (XANAX®)
9
H3C 1 N 2
5 12
N3
4
10
N 3
4
8
Cl
7
6
N5
8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin


With sedative-hypnotic and antianxiety
activities.
duration of action is short. Why?? .


It is rapidly metabolized by hydroxylation of
triazolomethyl group.
This metabolite is active but it is rapidly
conjugated.
H3C
N
HOH2C
N
N
N
N
N
Hydroxylation
Cl
N
Cl
N
7- BROMAZEPAM (CALMEPAM®)
O
H
N
N
Br
2
N1
7-Bromo-1,3-dihydro-5-(2-pyridyl)-2H1,4-benzodiazepin-2-one

Used mainly as anxiolytic.
SAR

Position 1:- N- atom is essential
for activity


N-substitution must be small
X
alkyl group.
Position 2:- the carbonyl group
is essential for the interaction
with B2 receptors
9
R
1
N
8
7
6
5
O
2
3
N4
• Position 3:- the OH or COO- is optimal, The
presence of alkyl →↓ activity.

Position 4, 5: Saturation of 4,5-double bond or its shift to 3,4position →↓activity.
 A phenyl at position 5 →↑activity.
 Ortho or diortho substitution of the phenyl
group
with
electron
withdrawing
group
→↑activity, but p-substitution →↓activity.
 Annelation of the 1,2-bond of the diazepine ring
with triazole or imidazole ring afforded active
compounds with higher affinity for B2 receptors
and short duration.
 Isosteric substitution of the henyl group with
other
heterocyclic
structure
→active
compounds.

Position 7:

electron
withdrawing
Position 6,8,9:


The presence of
group →↑activity.
must be remained unsubstituted.
The benzene ring of the benzodiazepine
structure could be substituted with other
heterocyclic ring →active compounds
Substitution of 1,4-benzodiazepin with 1,5benzodiazepine →active compounds.
Examples of benzodiazepines that are used in
mainly as anticonvulsants:
 1- Diazepam
 2-Lorazepam
 3-Clonazepam
 4-Clorazepate dipotassium
 5-Midazolam


All exert their activity through enhancing the
effect of GABA at GABA A receptors.
6-Miscellaneous Anticonvulsants
1)CARBAMEZEPINE (TEGRETOL®)
1
c d e
b
f
g
a
N5
6
O
2
4
3
NH2
5H-Dibenzo[b,f]azepine-5-carboxamide



One of the most saftest and effective agent.
It is equal in efficacy to phenytoin in controlling
seizure.
Act by blocking Na+-channels →prolong the
inactivation of Na+-channels
→↓ Na+-influx
→↓depolarization
and
neuronal
conductance
→↓spreding of seizures.
2) VALPROIC ACID (DEPAKIN®)
1
C3H 7
C
H3C
OCONH2
2
3
OCONH2
2-Methyl-2-n-propyl-1,3-propandiol dicarbamate
It has a satisfactory margin of safty and good
potency.
 Act by potentiate the inhibitory effect of GABA
and by blocking Na+-channels

With best wishes