Download Drugs Acting on CNS

Drugs Acting on CNS
CNS Depressants
A- Sedative & Hypnotics
They are divided into:1.
Barbiturates
2.
Non-Barbiturates
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
C2H5
O
NH
1
O
R
R2
O
C2H5
NH
N
R3
O
C2H5
O
O
O
N
H
Phenobarbital
5-Ethyl-5-phenylbarbituric acid
O
C H
NH
N
O
H
Barbital
5,5-diethylbarbituric acid
2 5
NH
O
O
N
CH3
Mephobarbital
5-Ethyl-5-phenyl-1-methylbarbituric acid
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 O
H3C
O
R1
CH3
NH
2
R
O
N
H
NH
H2C
O
H3C
C2H5
O
O
N
O
H
Aprobarbital
5-Allyl-5-isoproylbarbituric acid
O
NH
N
O
H
Amobarbital
5-Ethyl-5-isopentylbarbituric acid
CH3
O
H3C
NH
C2H5
O
N
O
H
Butabarbital
5-Ethyl-5-(1-methylpropyl)barbituric acid
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
CH3
CH
CH3
Short acting
barbiturates
Duration: 1-3 hours
Onset: 10-15 minutes
CH3 O
O
H3C
1
R
R2
O
H2C
CH3 O
NH
N
H
O
H3C
C2H5
O
N
O
H
Secobarbital
5-Allyl-5-(1-methylbutyl)barbituric acid
NH
N
O
H
Pentobarbital
5-Ethyl-5-(1-methylbutyl)barbituric acid
Generic/Trade
name
1- Pentobarbital
(Nembutal®)
2- Secobarbital
(Seconal®)
3-Cyclobarbital
(Phandoran®)
NH
O
O
NH
C2H5
O
N
O
H
Cyclobarbital
5-(1-Cyclohexenyl)-5-ethylbarbituric acid
R1
R2
Ethyl
H H2 H2
C C C CH3
CH3
-CH2CH=CH2
Ethyl
H H2 H2
C C C CH3
CH3
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
metabolicconversion 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
With best wishes