BENZODIAZEPINES
Mahpara Gondal (Senior Lecturer)
Rashid latif College of Pharmacy 1
CONTENT….
Introduction.
History.
Types.
Synthesis.
Mechanism of Action.
Uses.
Parent compound.
Requirement of SAR Study.
SAR Study.
Conclusion.
2
References.
3
BENZODIAZEPINES
The term benzodiazepine is the chemical name for
the heterocyclic ring system, which is a fusion
between the benzene and diazepine ring systems.
Under Hantzsch–Widman nomenclature,
a diazepine is a heterocycle with two nitrogen atoms,
five carbon atom and the maximum possible number
of cumulative double bonds. The "benzo" prefix
indicates the benzene ring fused onto the diazepine
ring.
4
CONTD….
Left: The 1,4-benzodiazepine ring system. Right: 5-phenyl-1H-
benzo[e][1,4]diazepin-2(3H)-one forms the skeleton of many of the most
common benzodiazepine pharmaceuticals, such as diazepam (7-chloro-1-
methyl substituted)
5
HISTORY….
The first benzodiazepine, chlordiazepoxide (Librium), was
synthesized in 1955 by Leo Sternbach.
Following chlordiazepoxide, diazepam was synthesized in
1959 and marketed by Hoffmann–La Roche under the
brand name Valium in 1963, and for a while the two were
the most commercially successful drugs.
The molecular structure of chlordiazepoxide, the
first benzodiazepine. It was marketed
by Hoffmann–La Roche from 1960 branded
as Librium.
6
CONTD……
The introduction of benzodiazepines led to a
decrease in the prescription of barbiturates, and by
the 1970s they had largely replaced the older drugs
for sedative and hypnotic uses.
In 2010, formerly classified documents from
a Medical Research Council (UK) meeting of experts
emerged and revealed that benzodiazepines could
cause brain damage in some people similar to that
which occurs from alcohol abuse and failed to follow-
up with larger clinical trials.
7
ADVANTAGES OF BENZODIAZEPINES
OVER BARBITURATES…..
BZDs have high therapeutic index. Ingestion of
even 20 hypnotic doses does not usually
endanger life.
Hypnotic does not affect respiration or
cardiovascular functions. Higher doses produce
mild respiration & hypotension which is
problematic only in patients with respiratory
insufficiency & cardiac abnormality.
BZDs have practically no action on other body
system 8
CONTD……
BZDs cause little distortion of sleep
architecture.
BZDs do not alter disposition of other drug by
microsomal enzyme induction.
They have lower abuse liability: tolerance is
mild, psychological & physical dependence &
withdrawal syndrome are less marked.
A specific BZDs antagonist flumazenil is
available which can be used in case 9of
poisoning.
MOA OF BENZODIAZEPINES
Benzodiazepines work by increasing the efficiency of a
natural brain chemical, GABA, to decrease the
excitability of neurons. This reduces the communication
between neurons and, therefore, has a calming effect on
many of the functions of the brain.
GABA controls the excitability of neurons by binding to
the GABAA receptor. The GABAA receptor is a protein
complex located in the synapses of neurons. All
GABAA receptors contain an ion channel that
conducts chloride ions across neuronal cell
membranes and two binding sites for
the neurotransmitter gamma-aminobutyric acid (GABA),
while a subset of GABAA receptor complexes also contain
10
a single binding site for benzodiazepines.
CONTD……
Binding of benzodiazepines to this receptor complex
promotes binding of GABA, which in turn increases the
conduction of chloride ions across the neuronal cell
membrane. This increased conductance raises
the membrane potential of the neuron, resulting in
inhibition of neuronal firing.
Schematic diagram of the 11
(α1)2(β2)2(γ2)
GABAA receptor complex
TYPES…..
Benzodiazepines
Hypnotic Antianxiety Anticonvulsant
Diazepam. Diazepam. Diazepam.
Flurazepam. Chlordiazeperoxide. Lorazepam.
Alprazolam. Lorazepam. Clonazepam.
12
SAR
RING A
• It is believed to
participate in pi-pi bonding
with aromatic residue of
aromatic amino acids of the
receptor
• The substitution on this ring
produces varied effect on
binding with the receptor,
however such effects are not
predictable on the basis of
electronic and stearic properties
13
CONT…
• An electronegative group (halo or
nitro) substituted at 7-position
markedly increase activity and
binding affinity
• Substitution on 6,8 and 9 decrease
the activity
• On the other hand 1-4 diazepine
derivative having ring A replaced
with hetrocyclic ring have weak
activity and affinity as compared to
phenyl derivatives
14
RING B
A proton accepting group (carbonyl
oxygen) at 2- position of ring B is
necessary to interact with receptor histidine
residue that act as proton donor and help in
ligand binding
Electron donating group must be in the
same plane with electronegative group on
ring A, favoring a coplanar spatial
orientation of two moieties Substitution of
O with S effect selective binding GABA
BZR sub-populations but anxiolytic activity
is maintained
Substitution 3-position methylene or imine
nitrogen is sterically unfavorable
Derivatives having 3-hydroxy moiety
have comparable potency to non- 15
hydroxylated analogue but are excreted
faster
CONT…
Esterification of 3-hydroxy
moiety is possible without loss
of activity
1-poition amide nitrogen and its
substituent are not required for in
vitro binding with BZR because
many N-alkyl side chains don’t
decrease BZR affinity Neither 4,5
double bond nor the nitrogen of 4-
position is required for activity
If C=N is reduced BZR
affinity is decreased but the 16
derivatives again oxidized in
the body to C=N
RING C
The 5-phenyl ring C is not required for
binding to the BZR in vitro, however,
this aromatic ring contribute favorable
hydrphobic or steric interactions to
receptor binding and its relationship to
ring A
Substitution at 4' (para
position) is unfavorable for
activity, however, ortho
substitution is not detrimental to
agonist activity
17
CONTT..
Annelating the 1,2 bond of ring B with an
additional electron rich ring such as triazole
(alprazolam) or imidazole (midazolam)
results in pharmacologically active
benzodiazepine derivatives with
high affinity to BZR
triazole imidazole
18
19
PARENT STRUCTURE…..
R1
R2
1 2
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
5' 3'
4'
20
SAR STUDY….
Seven membered imino ring B was essential
for its affinity towards the BZ-binding site.
R1
R2
1 2
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
3' 21
5'
4'
CONTD……
Additionally,the carbonyl group at position
2, and the 4,5 double bond within the ligand
have also been shown to substantially
contribute to the binding affinity of the
R1
compound. 1 2
R 2
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
Required for activity
R2' 6'
2'
C 22
5' 3'
4'
CONTD……
Shiftof double bond to the 3,4 position
decreases activity.
R1
R2
1 2
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
5' 3'
4' 23
CONTD……
An electronegative Substituent at position 7
is required for activity, more the
electronegativity higher will be the activity.
R1
R2
1 2
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
5' 3' 24
4'
CONTD….
Positions at 6,8 & 9 should not be substituted.
R1
R2
1 2
9 N C
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
5' 3' 25
4'
CONTD….
A phenyl at position 5 promotes activity. If this phenyl
group is ortho or diortho (2’ , 6’) substituted with
electron attracting substituents, activity increase.
But para substitution decreases activity greatly.
R1
R2
1 2
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C 26
5' 3'
4'
CONTD….
R1
R2
1 2
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
5' 3'
4'
Alkyl substitution at position 3 decreases activity
except hydroxy group. 27
CONTD….
The presence or absence of 3-hydroxyl is important
pharmacokinetically. Compounds without hydroxyl
group are non polar, have long half lives & undergo
hepatic oxidation.
R1
R2
1 2
9
N C H/COO– OH
8
A B C
3
•Polar.
7
R7 6 5
C N
4 •Non polar. •Readily converted to the
excreted glucuronide.
R2' 6'
2'
•Long half-lives.
C
3'
5'
4'
• Undergo hepatic 28
oxidation.
CONTD….
The 2-carbonyl function is optimal for
activity.
R1
1 2 O
9 C
N
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
5' 3'
4'
29
CONTD….
R1 substitution should be small.
R1 R2
1 2
9
N C
8
3
A B C R3
7
C N
R7 6 5 4
R2' 6'
2'
C
5' 3'
4'
30
SAR STUDY OF BENZODIAZIPINES
R1 R2 R3 R4
a CH3 H H Cl
b CH3 H F Cl
c H H H NO2
d H H Cl NO2
a.diazepam
b.flutoprazepam
c. nitrazepam
d. clonazepam 31
SAR STUDY OF T R IA Z O LE OR IMIDA ZOL E
DRUGS R1 R2
H H
estazolam
CH3 H
alprazolam
CH3 Cl
trizolam
CH3 F
Midazolam
32
WHICH DRUG?
33
FEW WORDS ABOUT
CLONAZIPAM…
Clonazepam is a benzodiazepine derivative
having anticonvulsant, muscle relaxant, and
very potent anxiolytic properties.
Clonazepam is classified as a high potency
benzodiazepine and is sometimes used as a
second line treatment of epilepsy. Clonazepam,
like other benzodiazepines, while being first
line treatments for acute seizures, are not first
line for the long-term treatment of seizures
due to the development of tolerance to the 34
anticonvulsant effects.
CONTD……
Clonazepam is a chlorinated derivative
of nitrazepam and therefore a chloro-
nitrobenzodiazepine.
Pharmacokinetic data
Bioavailability 90%
Protein binding ~85%
Metabolism Hepatic CYP3A4
5-(2-chlorophenyl)-7-nitro-2,3- Half-life 18-50 hours
dihydro-1,4-benzodiazepin-2-one Excretion Renal
35
DIAZEPAM
Diazepam is a classical aryl 1,4-
benzodiazepine with no hydrogen
bond donors, three acceptors, a low
molecular weight (MW = 284.7),
While it is now accepted that these
properties are consistent with good
CNS penetration and drug
metabolism properties.
36
APPROVED INDICATIONS
Diazepam is approved for the treatment of
anxiety, acute alcohol withdrawal, skeletal
muscle spasm, and convulsive disorders (e.g.,
status epilepticus).3 It is used off-label for
numerous other conditions including insomnia,
restless leg syndrome, and pre/post-operative
sedation
37
ADVERSE EFFECTS
Serious and fatal adverse events associated with
diazepam are extremely rare and are most often
a consequence of interaction with another drug
(such as opiates or alcohol). The most common
fatal events are respiratory arrest and prolonged
seizures resulting from prolonged habitual use,
rather than acute overdose.
38
FLUTOPRAZEPAM
Flutoprazepam (Restas) is a drug
which is a benzodiazepine. Its muscle
relaxant properties are approximately
equivalent to those of diazepam -
however, it has more
powerful sedative, hypnotic, anxiolytic
and anticonvulsant effects and is
around four times more potent by
weight compared to diazepam.
It is longer acting than diazepam due
to its long-acting active metabolites. It
is used for the treatment of
severe insomnia and may also be used 39
for treating stomach ulcers.
NITRAZEPAM,
Nitrazepam, sold under the brand
name Mogadon among others, is
a hypnotic drug of
the benzodiazepine class used for
short-term relief from severe,
disabling anxiety and insomnia. It
also has sedative (calming)
properties,[5] as well
as amnestic (inducing
forgetfulness), anticonvulsant,
and skeletal muscle relaxant effects.
40
NITRAZEPAM
Nitrazepam is a nitrobenzodiazepine. It is a 1,4
benzodiazepine, with the chemical name 1,3-
Dihydro-7-nitro-5-phenyl-2H-1,4- benzodiazepin-
2-one.
It is long acting, lipophilic, and metabolised
hepatically by oxidative pathways
Nitrazepam is largely bound to plasma proteins
Nitrazepam overdose may result in stereotypical
symptoms of benzodiazepine overdose including
intoxication, impaired balance and slurred
speech.
41
CLONAZEPAM
Clonazepam is a
synthetic benzodiazepine derivative
used for myotonic or atonic seizures,
absence seizures, and photosensitive
epilepsy, anticonvulsant Clonazepam
appears to enhance gamma-
aminobutyric acid receptor responses.
Common side effects include
sleepiness, poor coordination, and
agitation. Long-term use may result
in tolerance, dependence,
and withdrawal symptoms if stopped
abruptly. 42
ESTAZOLAM
Estazolam is a triazolo-
benzodiazepine with
anxiolytic, anticonvulsant,
hypnotic, and muscle
relaxant properties.
Estazolam is an orally
available benzodiazepine use
d to treat insomnia.
43
CLINICAL USES
Estazolam is prescribed for the short-term
treatment of certain sleep disorders. It is an
effective hypnotic drug showing efficacy in
increasing the time spent asleep as well as
reducing awakenings during the night.
Side effects
A hang-over effect commonly occurs with next
day impairments of mental and physical
performance. Other side effects of estazolam
include somnolence, dizziness, hypokinesia, and
44
abnormal coordination
ALPRAZOLAM
The chemical name of alprazolam is
8-Chloro-1-methyl-6-phenyl-4H-s-
triazolo [4,3-α] [1,4] benzodiazepine.
Alprazolam is mostly used in short
term management of anxiety
disorders, panic disorders,
and nausea due to chemotherapy.
45
TRIAZOLAM
The chemical name for triazolam is 8-
chloro-6-(o-chlorophenyl)-1-methyl-4H-s-
triazolo-[4,3-α] [1,4] benzodiazepine.
Triazolam is usually used for short-term
treatment of acute insomnia and circadian
rhythm sleep disorders.
Triazolam is also sometimes used as
an adjuvant in medical procedures
requiring anesthesia or to reduce anxiety
during brief events, such as MRI scans and
nonsurgical dental procedures.
46
MIDAZOLAM
Its IUPAC name 8-chloro-6-(2-
fluorophenyl)-1-methyl-4H-
imidazo[1,5-a][1,4]benzodiazepine.
Midazolam, marketed under the
trade name Versed, among others,
is a benzodiazepine medication used
for anesthesia, procedural
sedation, trouble sleeping,
and severe agitation. It works by
inducing sleepiness, decreasing
anxiety, and causing a loss of ability
to create new memories.[3] It is also
useful for the treatment of seizures 47
48
