Unit IV

Drugs acting on Central Nervous System

A. Sedatives and Hypnotics:
Benzodiazepines: SAR of Benzodiazepines, Chlordiazepoxide, Diazepam*, Oxazepam,
Chlorazepate, Lorazepam, Alprazolam, ZolpidemBarbiturtes: SAR of barbiturates,
Barbital*, Phenobarbital, Mephobarbital, Amobarbital, Butabarbital, Pentobarbital,
Secobarbital. Miscelleneous: Amides & imides: Glutethmide. Alcohol & their carbamate
derivatives: Meprobomate, Ethchlorvynol. Aldehyde & their derivatives: Triclofos sodium,
Paraldehyde.
B. Antipsychotics: Phenothiazeines: SAR of Phenothiazeines- Promazine hydrochloride,
Chlorpromazine hydrochloride*, Triflupromazine, Thioridazine hydrochloride,
Piperacetazine hydrochloride, Prochlorperazine maleate, Trifluoperazinehydrochloride.
Ring Analogues of Phenothiazeines: Chlorprothixene,Thiothixene, Loxapine succinate,
Clozapine.
Flurobuterophenones: Haloperidol, Droperidol, Risperidone. Beta amino ketones:
Molindone hydrochloride. Benzamides: Sulpieride.
C. Anticonvulsants: SAR of Anticonvulsants, mechanism of anticonvulsant action.
Barbiturates: Phenobarbitone, Methabarbital. Hydantoins: Phenytoin*, Mephenytoin,
Ethotoin. Oxazolidinediones: Trimethadione, Paramethadione. Succinimides:
Phensuximide, Methsuximide, Ethosuximide* Urea and monoacylureas: Phenacemide,
Carbamazepine* Benzodiazepines: Clonazepam. Miscellaneous: Primidone, Valproic acid,
Gabapentin, Felbamate
 Definatio
n
• A sedative drug decreases activity and
excitement of the patient and clams
anxiety by producing milddepression of
CNS without causing drowsiness or sleep

• A hypnotic drug produces drowsiness,

forcing the patient to sleep bydepressing
the
CNS , particularly the reticular activity
which
influences wakefulness
 Dose dependent
activity
• All sedative, hypnotic and GA depress the
CNS
• The observed effect depends on the dose
given to patient
• Small dose cause sedation (calmness)

• Medium dose cause hypnosis (sleepy)

• Larger dose causes surgical anesthesia

 Utilit
y
Sedatives counter various types of anxiety such
as
• Obsessive-compulsive disorder (OCD)
• Post-traumatic stress disorder (PTSD)
• Social anxiety disorder
• Specific phobias
Hypnotics is for insomnia. Insomnia is a
condition where person is not able to fall sleep
 Ideal properties of
hypnotics
1. Cause a temporary decrease in the level of
consciousness for the purpose of falling
asleep without any alteration to sleep cycle
2. Must not decrease or arrest respiration,
even at high doses
3. Cause no addiction, tolerance or
dependence
• sleep cycle : Sleep proceeds incycles of
light sleep and deep sleep
• Light sleep – NREM sleep, lasts for about
90 mins
• Easy to wake in this period
• Deep sleep – REM sleep, last 5 to 10 mins
• Difficult to wake in this time
 Drug
classification
1. Barbiturates :Phenobarbitone*
2. Benzodiazepines:
Alprazolam, Diazepam, Nitrazepam,
Lorazepa m
3. Non-Benzodiazepines: zolpidem, Zalephon
4. Others: paraldehyde, Glutethimide, Chloral
Hydrate
5. Herbal sedatives: Ashwagandha, Valerian
and passiflora
 Barbiturate
s
• All derivatives of Barbituric acid
• They are CNS depressants. They are
effective as anxiolytics, hypnotics,
anticonvulsants and analgesics.
• They have addiction potential, both
physical and psychological.
• Thus Benzodiazipines have largely
replaced them in term of sedative-hypnotic
 Type
s

Barbituric
Acid

Ultra
Long- shortacting
Acting
Intermediate Short
acting acting

Thiopental
sodium
Phenobarbita
l
Amobarbita Pentobarbita
l l
Factors effecting Duration of action as by the SAR
Phenobarbital Thiopental Sodium
Branched R group
Short ethyl chain Long chain of R group Total C =
Total carbon = 2 (not counting 7
aromatic)
Additional improvements to
Thiopental Sodium tofurther
decrease duration of action
•N methylation (potency also inc)
•Unsaturated R group
• Mode of action of barbiturates
1. They have positive allosteric effect at GABA
receptor. They bind at a different site than
GABA or Benzodiazepines and stimulate the
pharmacologic action of GABA which is the
inhibitory neurotransmitter in the
principal
CNS
2. They inhibit AMPA receptor, which binds
glutamate which is principalexcitatory
neurotransmitter in the CNS
3. At higher does they inhibit Ca2+ dependent
release of neurotransmitters
• Allosteric drugs bind the receptor at different site. They can
both stimulate or inhibit the receptor function.
• Agonist can only stimulate the receptor function
• Antagonist can only inhibit the receptor function
 Structure-Activity
• Barbituric acid itself does not possessany hypnotic
Relationship
properties.
•Activity requires a balance of acidic and lipophilic
properties.
To make the drug sufficiently acidic, both or at least one
of the two nitrogen must be unsubstituted
To make drug sufficiently lipophilic, the two hydrogen
atoms at position 5 : 5 must have the appropriate
substituent e.g.,
( alkyl or aryl groups)
The type of substituent's control 2 aspects of the drug
Potency
Duration of Action.
 O

HN NH Barbituric
acid

O O
Inactive inactive coz not lipophilic
enough

O O O

R
HN NH HN NH N NH

O O O O O O

R R R R
R
inactive active active
coz not lipophilic
enough O

R R
N N

O O

R R

Inactive coz not acidic

enough
 the total number of carbon atoms present in the two
groups at carbon 5 must not be less than 4 and more than
10 and influences onset of action and duration

Total carbon Duration of action

7-9 Rapid onset n shorter
duration
5-7 Intermediate duration
of action
4 Slowest onset and
longest duration of
action
 Only one of the substituent groups at position 5 may be
a
cyclic group.
O

HN C
C2
H
5
O C C

N C

O
CH3
Methylepentobarbita
l
The branched chain isomer exhibits greater activity but
shorter duration. The greater the branching, the more
potent is the drug (e.g., pentobarbital > amobarbital).
This Branched, cyclic or unsaturated alkyl groups reduce
duration of action due to increased ease of metabolic
inactivation

Pentobarbita Amobarbita
l l
(iv) Double bonds in the alkyl substituent groups
produce compounds more readily vulnerable to tissue
oxidation ; hence, they are short-acting.

Pentobarbital
Sodium
Aromatic and alicyclic moieties exert greater potency
than the corresponding aliphatic moiety having the same
number of carbon atoms.

O 2
HN C 1
C2
H 4
6
5
C
O C C 6
5 HN C 3
1 more potent C2
H
5
HN C than 5
C C
O 2 4 O N O
H
3
Short chains at carbon 5 resist oxidation and hence are
long-acting. Long chains are readily oxidized and thus
produce short-acting barbiturates.

Barbita Pentobarbital
l Sodium
Inclusion ofa halogen atom in the 5-alkyl moiety enhances
activity.

Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and
SO3H) in the 5-alkyl moiety reduces potency considerably.

Methylation of one of the imide hydrogens enhances onset and

reduces duration of action

Methylepentobarbita
l
The replacement of O-atom with an S-atom, at C- 2
position of the barbiturates significantly enhances the lipid
solubility. The resulting modified versions of the
barbiturates thus obtained exert a rapid onset of activity by
virtue of the fact that they attain maximal thiobarbiturate-
brain levels. Therefore, such drugs as ‘thiopental sodium’
find their profuse and abundant application as ‘intravenous
anaesthetics’.
O

HN C
C2
H
5
SNa HC C (CH2
)
C
H
23
CH
HN C
CH3
Thiopental O
sodium
Inclusion of more sulphur atoms (at C-2 and C-6) decreases
activity. Likewise replacement of Oxygen with Nitrogen
abolishes activity

NH

R R
N N

Inactiv
O O e
R R
 Phenobarbita
l
• Phenobarbital or phenobarbitone
is a barbiturate which is most
widely used anticonvulsant
worldwide and the oldest still
commonly used.
O
C2
H
5
C C NH

C C
O N O
H

Phenobarbit
al
• It also has sedative and hypnotic
properties but, as with other
barbiturates, has been outdated by the
benzodiazepines for these indications.
• first-line for partial and generalized
tonic- clonic seizures
• first line choice for the treatment of
neonatal seizures
• Sedation and hypnosis are the
principal side effects of
phenobarbital. Also dizziness,
nystagmus and ataxia are common.
• In elderly patients, it may cause
excitement and confusion while in
children, it may result in paradoxical
hyperactivity.
• Overdose may also lead to pulmonary
edema and acute renal failure
• It is one of the longest-acting
barbiturates available – it
remains in the body for a very
long time (half-life of 2 to 7
days) and has very low protein
binding
• Phenobarbital is metabolized by
the liver, mainly through
hydroxylation and
glucuronidation
• It is excreted primarily by the
kidneys
 O

i)Acid hydrolysid C OC 2
H
CH2
CN 5
CH2
ii) EtOH

Benzyl Ethyl phenyl

cyanide acetate

Diethyl
EtOH oxalate
and Na C 2

Synthesis
H
O
5 C C OC 2
H
5
(-OC2H)
5 O O
O
O

of
H
C COC 2H5 Distilled at 180O C
CH C OC 2
H
5
C OC 2
H
5
(-CO) C C OC 2
H
5

Phenobarb
O
O O
Phenyl malonic ester
Diethyl phenyl-oxyalo-
acetate

i tone
C2
H
-
B
5r
(
et
h
y
lb
r
om
i
de
)
-HBr C2
H
-
ON
a(
s
od
i
u
me
th
o
x
id
e
)
5

O O

C 2H5 O C2
H
5 C
C
C NH
C C H
O
C
H
2
5N
2 N
H
2
u
r
e
a
C C
C OC 2
H
5
O N O
-2 EtOH H
O
Phenobarbita
Ethylphenyl malonic l
ester
 O

HN C

Thiopental
C 2H5

NaS HC C (CH2
)
C
H
23

sodium
CH
HN C
CH3

• Ultra short acting barbiturate mins)

(5-10O

• Rapid action (10 -15 sec) and

rapid recovery
• Used mainly as inducing
anesthetic
•anesthetic state maintained by
• has no analgesic properties
inhalation anesthetic eg N20
•it is a poor muscle relaxant
• it possesses potent anticonvulsant activity it
may be given to treat epileptic seizures that do
not respond to other therapy.
• It is stored as a solid white salt and needs to be
prepared in sterile water to inject the patient
• Rapid recovery not due to rapid metabolism
• It is due to lowered concentration caused by
redistribution of drug from brain to blood. This
is made possible becoz of the salt form of drug
• Dose: 3 to 7 mg/kg.
• It does not have any direct toxic effects
on the liver or kidney
• Although it crosses the placenta it is a
safe agent for induction in pregnancy
Synthesis of Thiopental
sodium
i) Preparation of Diethyl ester of ethyl-(1-methyl
butyl) malonic acid
O O

C2
HO C Na
C2H5-Br
C2
H
5O C H
-H 5
Ethyl
C Na C Bromide
C2
HO H
C2
H
5OH Sodium 5 - NaBr
Metal
Diethyl O O
malonat
e

O O
Br C-CH -CH
2 2-CH
3
C2
HO C C2
H
5 5 CH3 C2
H
5O C
C 2H5
C 2- C
Bromopentane
- HBr
C2
HO C-CH2
-
C
H-
CH H
5 23 C2
H
5O
CH3
O O
Diethyl ester of Diethyl ester of
ethyl- (1-methyl ethyl malonic
butyl) malonic acid
acid
ii) Preparation of Thiopental
sodium NH2
CH
OCC
HSC
O

25 2
5

NH2
C
H OC C-CH2
-
C
H-
CH
25 23 - 2 EtOH
CH3
D
i
e
t
hy
le
s
t
e
ro
f
e
th
y
l
-
(1
-O
T
h
i
o
ur
e
a
m
e
t
h
yl
bu
t
y
l)
m
al
o
ni
c
a
c
i
d
O
O
HN C
N C
C 2H5
C2
H
5
S C C
HS C C

HN C C-CH2
-
C
H-
C
2H
3
HN C C-CH2
-
C
H-
C
2H
3
CH3
CH3 O
Enol form O
Keto form
NaOH
O

HN C
C2
H
5 Thiopental sodium
NaS CH C

C-CH2
-
C
H-
C
2H
3
HN C
CH3
O
Thiamyla
l
• Ultra short acting barbiturate
• Rapid action but not rapid recovery due to high
lipophilicity and subsequent drug accumulation
in the fatty tissues
• Used mainly as inducing anesthetic in lab
animals
• anesthetic state maintained by inhalation
anesthetic eg N20
• Use limited toVeterinary field. Only its sodium
salt is used in humans
 Benzodiazepine
s
•Chemically they are a fusion of a benzene ring and a
diazepine ring

•Benzodiazepines enhance the effect of the GABA at

the GABAA rec eptor,resu l
tingin
sedative, hypnotic (sleep-inducing), anxiolytic (anti-
anxiety) anticonvulsant, and muscle relaxant properties

•useful in treating anxiety, insomnia, seizures,

muscle spasms, alcohol withdrawal and preanesthetic
• are safer than barbiturate and not additive
 MOA of
benzodiazepines
1.They have positive allosteric effect at GABA receptor.
They bind at a different site than GABA or
Benzodiazepines and stimulate the pharmacologic action
inhibitory neurotransmitter
of GABA which is the principal
in the CNS

2.They block reuptake of Adenosine which is sedating

neurotransmitter, thus promoting its sedative action.

Attach to and directly block the Acetylcholine (ACh)

receptors in the hippocampus thus causing amnesia.
(Hippocampus is where memory is stored and processed.
This is how date rape drug Flunitrazepam works)
SAR of
benzodiazepinez
R2= carbonyl
group
( C=O)
Mostly Cl or NO2 is used at position
7
But para substitution (position 4’) decreases
activity
(Note--> inclusion of OH,NH3,SO4,PO4, COOH groups increase
polarity)
 Types of
Basedbenzodiazepines
on drug elimination (metabolism + kidney filtration)
, 3 category of benzodiazepines exist

Half life example

Long acting > 24 hrs Diazepam,Nitrazepam
chlordiazepoxide, flurazepam
Intermediate acting 12-24 hrs alprazolam, lorazepam
clonazepam, flunitrazepam,
Short acting < 1-12 hrs midazolam and triazolam.

longer-acting benzodiazepines are recommended for

the treatment of anxiety
Short- and intermediate-acting are preferred for the
treatment of insomnia;
Midazola
m
• Midazolam has a rapid onset of action, high
effectiveness and low toxicity level and fast recovery
time
• Properties: It has potent anxiolytic, amnestic,
hypnotic, anticonvulsant, skeletal muscle relaxant,
and sedative properties
• Uses: Used for treatment of acute seizures, moderate
to severe insomnia and for inducing sedation and
amnesia before medical procedures
• used mostly as a premedication for sedation and less
commonly for induction or maintenance of anesthesia.
• MOA- alloteric GABAA e nhan cer
 Diazepa
•
m
Long acting benzodiazepine (>20 hrs)
• due to high blood protein binding of 98.5% which reduces rate
of elimination and it’s metabolic product is also active
• Properties: It has anxiolytic, anticonvulsant, hypnotic -
sedative, skeletal muscle relaxant, and amnestic properties
• Uses :anxiety, panic attacks, insomnia, seizures , muscle
spasms (such as in tetanus cases), restless legs syndrome,
alcohol withdrawal, opiate withdrawal syndrome
• Not used for long term epilepsy due to development of
tolerance
• Avoid during pregnancy
• MOA – Allosteric GABAA en h ancer
 Lorazepa
• m
high-potency, intermediate acting duration
benzodiazepine drug
Properties: anxiolysis, short term
amnesia, sedation/hypnosis, anticonvulsion, muscle
relaxation
Uses:
• short-term treatment of anxiety, insomnia, acute
seizures, sedation of aggressive patients
• to decrease the likelihood of agitation and
seizures in patients who have overdosed on
stimulant drugs
• lorazepam has advantage over diazepam, as in
– Better at ending seizures and
– more prolonged anticonvulsant effect
 Lorazepa
m
• lorazepam is removed from the blood more
rapidly than many other benzodiazepines,
there is less chance that lorazepam
concentrations in blood will reach high
levels and become toxic
• MOA- alloteric GABAA en h ancer
 Alprazola
m
• It belongs to intermediate acting benzodiazepine
• Properties: It has potent
anxiolytic, amnestic, hypnotic, anticonvulsant,
skeletal muscle relaxant, and sedative properties
• Main uses: Alprazolam is used for the treatment of
anxiety disorders and panic attacks
• can cause fetal abnormalities and should not be
used in pregnancy
• It is excreted in breast milk and should not be used
by women who are nursing
• MOA- alloteric GABAA e nha ncer
 Nitrazepa
m
• A long acting benzodiazepine
• Properties: It has anxiolytic, hypnotic
anticonvulsant, sedative, skeletal muscle -
relaxant,
• and
Uses:amnestic properties
Nitrazepam is used to treat short-term
sleeping problems (insomnia) and short term
management of epilepsies
• Nitrazepam is not suitable for use in the elderly,
children, pregnant women, or those with chronic
obstructive pulmonary disease
• MOA- alloteric GABAA enh a ncer
Barbiturates vs
Benzodiazepines
Barbiturates Benzodiazepines
They cause high physiological and They cause very less physiological and
psychological dependence psychological dependence

Long term use avoided due to toxicity Long term use is relatively safe
Sleep induced by it causes hangover Sleep induced by it is just like natural
effect after waking up sleep and is refreshing to wake up

Increase duration of GABA Cl channel Increase frequency of GABA Cl channel

opening opening

High Respiratory depression Manageable Respiratory depression

 Different alpha units of GABAA
have d iffe re n t
e ffe c ts
GABA A receptors containing GABA A receptors containing
alpha 1 subunits are involved alpha 2 or alpha 3 subunits
in sleep. are involved in anxiety.
 GABAA A
l
p
ha
1S
e
le
c
ti
v
eH
yp
no
t
i
cs
– M O
A
of
Za
l
e
pl
o
nan
d
• Zolp
The GABAi
A
d
e
m
r
e
c
ep
t
o
rc
o
n
t
ai
n
6d
if
f
e
r
en
t
al
p
ha
sub units
• Benzodiazepines bind to four of GABAA al
ph a
sub units: alpha 1,al
p ha 2,a l
p h a 3a ndalpha 5.
• Each of these subunits is associated with different
effects, and thus benzodiazepines not only cause
sedation but are also anxiolytic, cause muscle
relaxation, and have alcohol potentiating actions.
• The hypnotics zaleplon and zolpidem bind
selectively to GABA-A receptors that contain the
alpha 1 subunit (sleep).
Advantages over benzodiazepines
• A relatively short half life so one does not wake
up with a "hangover" the following day
• Having little effect on sleep staging, allowing the
individual to obtain approximately the same
amount of time in each stage of sleep as one
would without the medications
• Less likely to cause addiction, withdrawal, or
tolerance relative to older sleeping medications.
• These drugs are very lipophillic which
increases absorption into brain
• They are metabolized by liver into water
soluble metabolites which is rapidly
cleared out in urine and thus avoid
accumulation

Zolpide Zalepho
m n
•Zalephon : hypnotic dose 6-10 mg Used as
hypnotic drug
Good at inducing sleep but not good at
maintaining it since it has short elimination half
life
•Zolpidem : hypnotic dose 5-10 mg Used as
hypnotic drug
Slower acting but maintains effect overnight
period due to long elimination half life
 Paraldehyd
• e cyclic trimer of
Paraldehyde is the
acetaldehyde molecules. It is a colorless liquid
and sparingly soluble in water and highly
soluble in alcohol.
• Properties: It has an effective anticonvulsant,
hypnotic and sedative
• MOA:
Paraldehyde increases the effects of GABA, a
inhibitory neurotransmitter that depresses CNS,
at the GABAa receptor and decreases levels of
glutamate, which is stimulatory neurotransmitter
that excites CNS
Uses:
•to induce sleep, and is also used to calm psychiatric
patients
•it is used to prevent hallucinations and tremors caused
due to alcohol withdrawal
•used to control seizures in infantsm not responding to
phenobarbitone and phenytoin,
•Unlike diazepam and other benzodiazepines, it does not
suppress breathing at therapeutic doses and so is safer
when the patient's breathing is already compromised.
•It is very addictive and Paraldehyde also can stress the
gastrointestinal tract so that a patient can develop ulcers
H3
COC
H
3
•Synthesi O
H2SO4
•s O O
H3
CC
H
3
PARALDEHYD
ACETALDEHYD E
E
CH 3
 Glutethimid
e
• Properties: sedative, hypnotic
• Use: was used for insomnia but rarely prescribed
today just as likely to cause addiction and
caused severe withdrawal symptoms as
barbiturates.
• When taken with codeine, it stimulates
metabolic conversion of codeine into morphine,
which is used for its hallucinogenic effect
• MOA: It binds at the GABAa receptor which
increases the effects of GABA which is a
inhibitory neurotransmitter that depresses CNS
 Cl OH Cl OH

Chloral
metabolize
Cl C CH d Cl C CH2
OH
Cl

Hydrate
Cl
Chloral Trichloroethanol
Hydrate (Active compound)

4 Cl2 + C H
2 5O H + H2O → ClC
3 CH(O H)2+ 5 HC l
• Synthesis
Chloral hydrate is metabolized to trichloroethanol, which is
responsible for its physiological and psychological effects.
Higher doses can depress respiration and blood pressure.
Properties: seadtive, hypnotic
Use:
It has a very narrow therapeutic window making this drug
difficult to use. Instead benzodiazepines are preferred.
• short time (no more than 2 weeks) treatment of insomnia
• Used in organic synthesis as a reagent
MOA: It binds at the GABAa receptor which increases the
effects of GABA which is a inhibitory neurotransmitter that
depresses CNS
 Miscellaneous Sedative
Hypnotics
AMIDES AND IMIDES
Glutethimide,

Alcohols and Their Carbamate Derivatives

Ethchlorvynol
Meprobamate
Carisoprodol

ALDEHYDES AND THEIR DERIVATIVES

Paraldehyde
(Antipsychotics)
 Tranquilizers

Tranquilizer is a drug that is used to reduce anxiety, fear, tension, agitation,

and related states of mental disturbance.
Tranquilizers fall into two main classes, major and minor.

Major tranquilizers, which are also known as antipsychotic agents,

or neuroleptics, are so called because they are used to treat major states of
mental disturbance in schizophrenics and other psychotic patients.

Minor tranquilizers, which are also known as antianxiety agents,

or anxiolytics, are used to treat milder states of anxiety and tension in healthy
individuals or people with less serious mental disorders.
 Minor Tranquilizers
The principal minor tranquilizers are the benzodiazepines, among which are
diazepam (Valium), chlordiazepoxide (Librium), and alprazolam (Xanax). These
drugs have a calming effect and eliminate both the physical and psychological
effects of anxiety or fear.

Benzodiazepines’ mechanism of action is enhancing the action of the

neurotransmitter gamma-aminobutyric acid (GABA), which inhibits anxiety by
reducing certain nerve-impulse transmissions within the brain.

Other, less commonly used minor tranquilizers include meprobamate (Equanil,

Miltown) and buspirone (BuSpar).
 Minor Tranquilizers-Benzodiazepine Derivatives
Alprazolam (Xanax) Diazepam (Valium)
8-chloro-1-methyl-6-phenyl-4H - [1,2,
4]triazolo[4,3-a][1,4]benzodiazepine

7-chloro-1,3-dihydro-1-methyl-5-
phenyl-1,4-benzodiazepin-2(3H )-one
Chlordiazepoxide (Librax)

Lorazepam (Ativan)
7-chloro-2-methylamino-5-phenyl-
3H -1,4-benzodiazepine-4-oxide

7-chloro-5-(o-chlorophenyl)-1,3-dihydro-
3-hydroxy-2H-1,4-benzodiazepin-2-one:
Minor Tranquilizers-Benzodiazepine
Derivatives
Medazepam

7-chloro-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine

Oxazepam (Serepax)

7-chloro-3-hydroxy-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one
Minor Tranquilizers- Propandiol Dicarbamate
Derivatives
Meprobamate
It was the best-selling minor tranquilizer for a time, but has largely been
replaced by the benzodiazepines

[2-(carbamoyloxymethyl)-2-methyl-pentyl] carbamate
Tybamate
It is a prodrug for meprobamate

[2-(carbamoyloxymethyl)-2-methylpentyl] N-butylcarbamate
 Minor Tranquilizers- Cyclopyrrolones Derivatives
Zopiclone (Imovane)
 its active stereoisomer is eszopiclone (Lunesta)
 may be illegal to possess Zopiclone without a prescription

(RS )-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate

Synthesis: Reaction of pyrazine-2,3-dicarboxylic acid anhydride and

2-amino-5-chloropyridine followed by reduction with potassium borohydride and then
reaction with 4-methylpiperazine-1-carbonyl chloride gives Zopiclone.

O N O O
N H2
N Cl N N KBH4N N
O N Cl N Cl
N oxidation
oks.
N N
O O OH
O
Cl CO N N CH 3
N N
N Cl
N
O CO N N CH3
 Major Tranquilizers (Antipsychotics, or
Neuroleptics)
What are antipsychotic medications?
They are a range of medications that are used for some types of mental distress or disorder
- mainly schizophrenia and manic depression (bipolar disorder).
They can also be used to help severe anxiety or depression.

 They all affect the action of a number of chemicals in the brain called
neurotransmitters – chemicals which brain cells need to communicate with each other.

Dopamine is the main neurotransmitter affected by these medications. It is involved in

how we feel: It is also involved in the control of muscle movements.

If parts of the dopamine system become overactive, they seem to play a part in producing
hallucinations, delusions and thought disorder.

 The basic aim is to help feel better, without making one feel slowed down or drowsy.
 Antipsychotics
•Antipsychotics, known also as neuroleptics, and major tranquilizers, not only calm
severly disturbed pyschiatric patients but also relieve them of the symptoms of
their disease.
•Like other psychoactive drugs, neuroleptics do not cure mental diseases, but
rather treat only their target symptoms such as hallucinations or manias.

•Neuroleptics usually do not shorten the duration of psychotic phasis in

schizophrenia, but they do decrease the severity of mania and depressions.
•Contrary to the effect caused by hypnotic and sedatives, they do not cloud
consciousness or depress vital centers.
 Antipsychotics Typical Antipsychotics

•A class of antipsychotic drugs first

developed in the 1950s
•Commonly used but not the best and not
very selective
Examples:
Phenothiazine compounds Thioxanthene
compounds Butyrophenone compounds
Atypical Antipsychotics
•Also known as second generation
antipsychotics
•Less side effects (Parkinson like), more
selective
 Antipsychotics
The basic types of Antipsychotics are the phenothiazines, thioxanthines,
butyrophenones, clozapine, and rauwolfia alkaloids.

 The phenothiazines are the most widely used of these and include the drug
chlorpromazine.
They are thought to work by blocking the neurotransmitter dopamine in the brain.
This leads to a reduction of psychotic symptoms but can also result in unwanted side
effects

The butyrophenones, chief among which is haloperidol (Haldol), are similar to the
phenothiazines.

Another drug, clozapine, whose exact mode of action remains unclear relieves
schizophrenic symptoms in some patients who are not helped by phenothiazines.
Clozapine lacks the side effects of the phenothiazines but tends to induce an
infectious disease known as agranulocytosis.

 The rauwolfia alkaloids, such as reserpine, are no longer in common use.

 Antipsychotics

Mechanism of Action:
The mechanism of action of antipsychotic drugs are only partially known.
Although the antipsychotic drugs represent a wide variety of chemical
structures, their pharmacological and clinical activities are remarkably
similar.
The theory that most antipsychotic agents act as antagonists at pre- and
postsynaptic dopamine receptors, that is, by blocking dopamine from
binding to its receptor sites.
 Antipsychotics
PHENOTHIAZINE DERIVATIVES
First synthesized in 1950, chlorpromazine was the first drug developed with
specific antipsychotic action, and would serve as the prototype for the phenothiazine
class of drugs.

Phenothiazine derivatives are chemically characterized by a lipophilic fused

tricyclic system (the phenothiazine nucleus) linked through the nitrogen atom of the
central ring to a hydrophilic aminoalkyl substitutent (the tertiary basic side chain).

6 5 4
7
S 3
S
8 2
9 N
10 H
1 N R2
Chemical Abstract R1
system Chlorpromazine
 PHENOTHIAZINE DERIVATIVES

 Aliphatic compounds

Chlorpromazine (Thorazine Sonazine, Chlorprom, Largactil)

3-(2-chloro-10H -phenothiazin-10-yl)-N ,N -dimethyl-propan-1-amine

Triflupromazine (Clinazine, Vesprin)

N ,N -dimethyl-3-[2-(trifluoromethyl)-10H -phenothiazin-10-yl]propan-1-amine

 Piperidines
Thioridazine (Mellaril)
10-{2-[(RS )-1-Methylpiperidin-2-yl]ethyl}-2-methylsulfanylphenothiazine
 PHENOTHIAZINE DERIVATIVES
 Piperazines

Trifluoperazine
(Eskazinyl, Stelazine, Triftazin)

10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)-10H -phenothiazine

Fluphenazine
(Prolixin, Permitil, Modecate, Moditen)

2-[4-[3-[2-(trifluoromethyl)-10H -phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol
 PHENOTHIAZINE DERIVATIVES
Structure-Activity Relationships
It is postulated that phenothiazines interact with dopamine
receptors at three distinct sites, A, B, C. The order of
importance in terms of structure activity is B C A.

The pendent amine functionality (Site A)

R1 Intervening alkylchain between the
R2
N Y X centralring and the terminal amino
R3 group (Site B)
A tricyclic ring system with six- or
seven-membered central ring (Site C)
Site A Site B
Z Y=N, X=S
Site C
 PHENOTHIAZINE DERIVATIVES
Structure-Activity Relationships
SITE B
•A three carbon atom chain is needed for optimum neuroleptic activity
•This alkyl group should be bonded to a nitrogen atom
•A substituent at 2-position of this 3 carbon atom chain affects activity.
Whe R1 isa H at
om the ac t
ivit
y i
s op ti
m al.
•Whereas small alkyl substituents such as methyl are tolerated at the
C2 carbon, larger substituents (for example R1
:ph eny l
, d i
m ethylam i
no )
thatrestr
ic t thefre erota t
iond e creaseneu rol
eptic

potency. Triflupromazine

R2 R1
N Y X
R3

Site A Site B
Z
Site C

Y=N, X=S
 Structure-Activity Relationships of Phenothiazines
SITE C
•The phenothiazine ring is not planar. For example, the angle between the
two phenyl planes is 159o in chlorpromazine and 141o in perphenazine.

•Phenothiazine ring is not necessary for neuroleptic activity. Other planar

tricyclic systems like thioxanthenes are active.

•Substituents at 2-position (X) of the phenyl ring improve activity. Electron

withdrawing substituents such as halogens, methoxy, acetyl, trifluoromethyl
increase activity.

• Substituents at 1, 3, 4-positions decrease activity.

X

6 5 4
CH 3
N S 3
7
H R
C N S 8 2
N CH 2 CH 2 9 1 10
N
H
ASite
Bölgesi Site C
C Bölgesi
Chemical Abstract
A Site B
B Bölgesi
system
 Structure-Activity Relationships of Phenothiazines
SITE A
Nature of the amino group
• The size and nature of the basic amino group has considerable influence on the
behavior of the phenothiazine neuroleptics, because the molecule has to fit into a
narrow space.

• A tertiary amine has optimal activity; presence of alkyl groups larger than methyl or
replacing methyl groups with hydrogen atoms decrease activity.

• On the other hand, if the nitrogen is part of a heterocyclic ring (such as inN -
methylpiperazine and piperidine compounds), neuroleptic potency may not be
reduced. The effective size of the piperazine ring for instance, is smaller than that of
the diethylamino group.

R2 R1
N Y X
R3

Site A Site B
Z
Site C
Chlorpromazine
 Synthesis of Chlorpromazine
 The synthesis begins with the reaction of 1,4-dichloro-2-nitrobenzene with
2-bromobenzenethiol. Hydrogen chloride is evolved as a by-product of this step and a
thioether is formed as the product.

In the second step the nitro group is reduced with hydrogen gas. Upon heating in
dimethylformamide (DMF) solvent, ring cyclization occurs.

 The 2-chloro-10H-phenothiazine thus produced is combined with

3-chloro-N,N-dimethylpropan-1-amine in the presence of sodium amide base to form
chlorpromazine.
 Antipsychotics - Butyrophenones
Haloperidol, the most widely used classical antipsychotic drug in this class
Droperidol, often used for neuroleptanalgesic anesthesia and sedation in
intensive-care treatment
Benperidol, the most potent commonly used antipsychotic (200 times more
potent than chlorpromazine)

Haloperidol (Haldol)
4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidyl]
-1-(4-fluorophenyl)-butan-1-one

Droperidol (Innovar)
1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,5,6-
tetrahydropyridin-4-yl]-1,3-dihydro-2H -benzimidazol-2-one

Benperidol
1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}- 1,3-
dihydro-2H -benzimidazol-2-one
Structure Activity Relationships of Butyrophenones
All butyrophenone derivatives displaying high antipsychotic activity have
the following general structure:
2
1
''3
'2
1 234 R
F C CH2
CH2N 4'
p
CH2 3
O R
•p -fluorobutyrophenone skeleton is essential for neuroleptic activity.

•All potent compounds have a fluorine substituent in the para position of the
benzene ring. Replacing F with other groups like Cl-, Br-, -OCH3
d
ec
r
e
as
e
s
act
ivi
ty
Structure Activity Relationships of Butyrophenones

•Replacement of the keto group by a thioketone group decreases

neuroleptic activity.
• Reduction of the keto group to alcohol decreases potency.
•Lengthening, shortening, or branching of the three carbon (propyl)
chain decreases neuroleptic potency.
•Variations are possible in the tertiary amino group without loss of
neuroleptic potency. Nitrogen atom is usually incorporated into a six
membered ring (piperidine, tetrahydropyridine, or piperazine), which
usually has another substituent in position 4.
•R2 group should be aromatic. R3 group helps with activity, could be a –
OH group as in the case of haloperidol.
haloperidol
2
1
''3
'
2
R
1 2 3 4
F pC CH2CH2
N
C
H
2
4'
O 3 R
 Antipsychotics – Thioxanthene Derivatives
5 10 4
6 S 3

7
2
8 9 1

•Structurally related to phenothiazine derivatives, they resulted from

isosteric replacement in chlorpromazine and analogs.

•Their pharmacological actions and adverse effects are very similar to

those of phenothiazine derivatives.

• Examples include chlorprothixene, flupentixol, and thiothixene.

Structure Activity Relationships of Thioxanthene Derivatives

The structure-activity relationship of the thioxanthene mimic that of the

phenothiazines:
•The thioxanthene ring is also nonplanar: the angle between the two
phenyl planes is 142o in chlorprothixene, 150o in flupentixol, and 142o in
thiothixene.

X
 Thioxanthene Derivatives
 Chlorprothixene (Cloxan, Taractan, Truxal) is a typical antipsychotic
drug of the thioxanthene class and was the first of the series to be synthesized

 Cis thioxanthene analog of chlorpromazine

Chlorpromazine
(Z) -3-(2-chlorothioxanthen-9-ylidene)-N N
, -dimethyl-propan-1-amine

 Flupentixol

(EZ) -2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol
 Atypical Antipsychotics
Neuroleptics having dopamine receptor-blocking properties are frequently
responsible for the development of movement disorders.

Atypical antipsychotics are newer antipsychotic agents that have a

pharmacological profile different from older or typical antipsychotic drugs.

They cause less extrapyramidal side effects compared to the older typical
antipsychotic drugs.

They are more effective in treatment-resistant patients and have a greater

efficacy to treat negative symptoms, compared to the typical antipsychotics.

The three most accepted atypical drugs are; clozapine, risperidone and
olanzapine
 Atypical Antipsychotics
Clozapine is an medication used in the treatment of schizophrenia, and is also
sometimes used off-label for the treatment of bipolar disorder. It is the first of the
atypical antipsychotics to be developed.
Clozapine (Clozaril, FazaClo) Olanzapine (Zyprexa)

8-Chloro-11-(4-methylpiperazin-1-yl)- 2-methyl-4-(4-methyl-1-piperazinyl)-
5H -dibenzo[b e, ][1,4]diazepine 10H -thieno[2,3-b ][1,5]benzodiazepine

Risperidone (Risperdal) Oxypertine (Equipertine, Forit)

4-[2-[4-(6-fluorobenzo[d ]isoxazol-3-yl)- 1-piperidyl]ethyl]-3-methyl-

2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one

Amisulpride (Amipride , Amival, Sulpitac)

5,6-dimethoxy-2-methyl-3-
[2-(4-phenylpiperazin-1-yl)ethyl]-
H
1 -indole
(RS )-4-amino-N -[(1-ethylpyrrolidin-2-yl)methyl]- 5-ethylsulfonyl-2-methoxy-benzamide
 RESERPINE AND RELATED ALKALOIDS
Reserpine was isolated in 1952 from the dried root ofRauwolfia serpentina
(Indian snakeroot) and is an indole alkaloid antipsychotic. It is now mainly of
historic interest in psychiatry.
It is less effective as a neuroleptic than the other drugs already discussed,
and it is now used only on occasions when patients can not tolerate other
classes of antipsychotic drugs.

Rezerpine

N H
O OCH3

N H O
CH3
O H OCH 3
H
H3
C
O
O OCH3
C OCH3

Rauvolfia serpentina
Anticonvulsants
Cellular and Synaptic Mechanisms of Epileptic
Seizures

(From Brody et al., 1997)

 Treatment of Seizures
Goals:
1. Block repetitive neuronal firing.
2. Block synchronization of neuronal discharges.
3. Block propagation of seizure.
Minimize side effects with the simplest drug
regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES
 Treatment of Seizures
Strategies:

Modification of ion conductances.

Increase inhibitory (GABAergic) transmission.

Decrease excitatory (glutamatergic) activity.

 Classification of CONVULSION
1. Generalized seizures: which essentially involve the entire
brain and do not have an apparent local onset.
2. Unilateral seizures: which involve one entire side of the body.
3. Partial seizures: that have a focus.
4. Erratic seizures: of the newborn.
5. Unclassified seizures: (severe seizures associated with high
mortality such that time does not permit a precise
categorization).
GABAergic SYNAPSE

Drugs that Act at the

GABAergic Synapse
GABA agonists
GABA antagonists
Barbiturates
Benzodiazepines
GABA uptake inhibitors

Goal : GABA Activity

GLUTAMATERGIC SYNAPSE

Excitatory Synapse.
Permeable to Na+, Ca2+ and
K+.
Na+ Magnesium ions block
Ca2+ AGONISTS channel in resting state.
GLU Glycine (GLY) binding
GLY
enhances the ability of GLU
or NMDA to open the
channel.
Agonists: NMDA, AMPA,
Kianate.
Mg++
Goal: GLU Activity
K+
 
 
 
 
 
 
 
GLUTAMATERGIC SYNAPSE

 
 
 
 
 
 
 
 
 
 
 
 Treatment of Seizures
Most classical antiepileptic drugs exhibit similar
pharmacokinetic properties.
Good absorption (although most are sparingly soluble).
Low plasma protein binding (except for phenytoin, BDZs,
valproate, and tiagabine).
Conversion to active metabolites (carbamazepine, primidone,
fosphenytoin).
Cleared by the liver but with low extraction ratios.
Distributed in total body water.
Plasma clearance is slow.
 Treatment of Seizures

1) Hydantoins: phenytoin
2) Barbiturates: phenobarbital
3) Oxazolidinediones: trimethadione
4) Succinimides: ethosuximide
5) Acetylureas: phenacemide
6) Other: carbamazepine, lamotrigine, vigabatrin,
7) Surgery, Vagus Nerve Stimulation (VNS).
Chemical Structure of Classical Antiseizure Agents
X may vary as follows:
Barbiturates O= C – N
Hydantoins -N–
Oxazolidinediones – O –
* Succinimides –C–
Acetylureas - NH2–
*(N connected to C2 )
 Treatment of Seizures
Structurally dissimilar drugs:
• Carbamazepine
• Valproic acid
• BDZs.
New compounds:
• Felbamate
• Gabapentin
• Lamotrigine
• Tiagabine
• Topiramate
• Vigabatrin
 SARs among Anticonvulsants

R and R' should both be hydrocarbon side chain.

If both R and R' are lower alkyls, the tendency is to be active against
absence seizures (petit mal) and not active against generalized tonic-
clonic (grand mal) or partial seizures.
If one of the hydrocarbon substituents is an aryl group, activity tends
to be directed toward generalized tonic-clonic and partial seizures
and not antiabsence activity.
A conformational analysis of the aryl-containing antigeneralized tonic-
clonic agents indicates that the conformational arrangement of the
hydrophobic groups is important.
 SARs among Anticonvulsants
A conformational analysis of the aryl-containing antigeneralized
tonic-clonic agents indicates that the conformational arrangement of
the hydrophobic groups is important.

R and R’ absence (petit mal) generalized tonic-clonic

(grand mal) or partial

Alkyl Groups active inactive

Aryl Groups inactive active
 Barbiturates

Phenobarbital and mephobarbital display enough anticonvulsant

selectivity for use as antiepileptics.
The metabolism of phenobarbital involves p-hydroxylation, followed by
conjugation.
Mephobarbital is extensively N-demethylated in vivo and is thought to
owe most of its activity to the metabolite phenobarbital.
In keeping with their structures, both agents are effective against
generalized tonic-clonic and partial seizures.
 Hydantoins

The hydantoins are close structural relatives of the

barbiturates, differing in lacking the 6-oxo group. They
are cyclic monoacylureas rather than cyclic diacylureas. As
a consequence of losing a carbonyl group, they are weaker
organic acids than the barbiturates, thus, aqueous
solutions of sodium salts, such as of phenytoin sodium,
generate strongly alkaline solutions.
The compounds have antigeneralized tonic-clonic
activity. Hydantoins with lower alkyl substituents
reportedly have antiabsence activity.
 Phenytoin and
Phenytoin Sodium

Is the first anticonvulsant in which it was clearly

demonstrated that anticonvulsant activity could definitely be
separated from sedative-hypnotic activity.
Acting as a sodium channel blocker.
The drug is useful against all seizure types except absence.
Is incompletely or erratically absorbed from sites of
administration due to its very low water solubility.
Metabolism proceeds by p-hydroxylation of an aromatic ring,
followed by conjugation.
 Actions of Phenytoin on Na + Channels

Na+
• Resting State

• Arrival of Action Potential

causes depolarization and
channel opens allowing Na+
sodium to flow in.

• Refractory State,
Inactivation
Na+
Sustain channel in
this conformation
 Oxazolidinediones

Replacement of the N-H group at position 1 of the

hydantoin system with an oxygen atom yields the
oxazolidine-2,4dione system.
The oxazolidinedione system has antiabsence activity,
although these compounds is substituted with lower alkyls.
Aryl substituted oxazolidine-2,4-diones have shown activity
against generalized tonic-clonic seizures.
Dermatological and hematological toxicities associated
with the group may be the problem.
 Trimethadione

Was the first drug introduced specifically for treating

absence seizures.
It is important as a prototype structure for antiabsence
compounds.
Dermatological and hematological toxicities limit its clinical
use.
The drug is metabolized by N-demethylation to the active
metabolite dimethadione.
Dimethadione is a calcium T channel blocker.
Dimethadione is a water soluble and less lipophilic and
thus is excreted unchanged.
 Succinimides

Succinimides (CH2
r
ep
l
a
ce
sO
)
h
a
ve
a
ct
i
v
i
ty
ag
a
i
n
s
t
generalized tonic-clonic, partial seizures absence, and
complex partial seizures . Three are now in clinical use.
 Ureas and Monoacylureas
Ureas and monoacylureas, have a long history of
producing compounds with anticonvulsant activity.
The numerical yield of clinically useful
compounds has not been great, however, most of
the simpler compounds have gone by the way.
For convenience of grouping, carbamazepine and oxcarbazepine
can be considered N,N-diacylureas.
 Carbamazepine
SAR can be viewed either as an ethylene-bridged 1,1diphenylurea or
an amido substituted tricyclic system.
The two phenyls substituted on the urea nitrogen fit the pattern of
antigeneralized tonic activity.
Mode of action: sodium channel block.
Carbamazepine is useful in generalized tonic-clonic and partial
seizures.
The drug has the potential for serious hematological toxicity, and it is used with
caution.
Metabolism proceeds largely through the epoxide formed at the (Z)
cis-stilbene double bond. In humans, the epoxide reportedly is
converted largely to the 10,11-trans-diol. The epoxide is a suspect in
the idiosyncratic reactions carbamazepine may produce (aplastic
anemia).
With this in mind, compounds designed to avoid the epoxide such as oxcarbazepine
were developed.
 Oxcarbazepine
Oxcarbazepine is reduced to the monohydroxy compound.
The monohydroxy compound is considered the major active
metabolite.
The drug is used against partial seizures.
The major mechanism of action is sodium channel block.
 Miscellaneous Agents

Many carboxylic acids have anticonvulsant activity,

although often of low potency, possibly in part because
extensive dissociation at physiological pH produces poor
partitioning across the blood brain barrier.
 Valproic acid
2-propylpentanoic acid (Depakene) has good potency and is used
against typical and atypical absence seizures and absence seizure
with generalized tonic-clonic seizure.
Mechanistically, the drug is a sodium channel blocker.
Metabolism is by conjugation of the carboxylic acid group and
oxidation of one of the hydrocarbon chains.
Many of the side effects are mild. Rare, but potentially fatal,
fulminant hepatitis has caused concern.
 Gabapentin
Despite the fact that gabapentin is a relative of GABA with
increased hydrophobic character; a binding site on calcium
channels has been identified.
The drug is said to have a good pharmacokinetic profile
and to cross the blood-brain barrier well.
It was introduced for adjunctive therapy of refractory
partial seizures and, secondarily, generalized tonic-clonic
seizures.
 Tiagabine (Gabitril)

It blocks GABA reuptake.

Its use is against partial seizures.
 Lamotrigine (Lamictal)
Lamotrigine has been found effective against refractory
partial seizures.
It is act by blocking sodium channels and preventing
glutamate release.
 Felbamate
It is a sodium channel blocker.
Felbamate has been used successfully in refractory
patients with generalized tonic-clonic seizures and
complex partial seizures.
The drug is associated with a serious risk aplastic anemia.
It is used with extreme caution after other anticonvulsants
have been tried and a careful risk-to-benefit has been
made.
 Zonisamide (Zonegran)Topiramate (Topamax)
Zonisamide and Topiramate have, respectively, the sulfonamide and
sulfate amido (sulfamate) as the small polar group and an extensive
hydrophobic group as the large end.
Both are sodium channel blockers. Zonisamide also blocks calcium-T
channels and Topiramate increases the effect of GABA and
antagonizes glutamate receptor. Each of the drugs is employed
adjunctively against partial seizures.
Ca2+ Channels
Ion Channels
Ca 2+ • Voltage-gated
• Multiple Ca2+ mediated
events
B
Drugs Used:
• Calcium Channel
Blockers

 : sites of N-linked glycosylation.

P: cAMP-dependent protein kinase
phosphorylation sites
SYNTHESIS
Carbamazepine is synthesized by direct reaction of