CENTRAL NERVOUS SYSTEM

SEDATIVE-HYPNOTICS

PHAR 206 Pharmaceutical Chemistry I

Prof. Dr. Ayla BALKAN

Spring 2022
CLASSIFICATION OF CENTRAL
NERVOUS SYSTEM DRUGS
• Drugs affecting the central nervous system display multiple activities.

• Based on their therapeutic usefulness, CNS drugs may be divided into

three categories.
• General CNS depressants
• General CNS stimulants
• Selective CNS Drugs
1.General CNS depressants
• These drugs effect by nonselective depression of the synaptic
structures including presynaptic and postsynaptic tissues.
Sedative-hypnotics and general analgesic drugs

2. General CNS stimulants

• These drugs exert their action non selectively by either of the
following two mechanisms:
• Blocked of postsynaptic inhibition or
• Direct neuronal excitation.
3. Selective CNS Drugs
• These drugs may be either depressants or stimulants, acting
by diverse mechanisms.

For example anticonvulsants, centrally acting relaxants,

analgesics and psychopharmacologic agents are selective
CNS drugs.
 SEDATIVE-HYPNOTICS

• These agents are general depressants.

• A sedative produces mild depression and calms anxiety
without causing drowsiness or impaired performance.
• A hypnotic compels the user to sleep a stronger form of
depression.
• Hypnotics are often referred to as sleeping pills, sedative
medications and sedative-hypnotics.
• This class of drugs cause’s drowsiness and facilitates the
initiation and maintenance of sleep.

• Classically, this chapter would be titled sedative-hypnotics,

however, due to the extensive use of benzodiazepines as
sedative –antianxiety drugs which are covered in an other
chapter.
• In this chapter will be limited to drugs primarily used as
hypnotics.
• The observed pharmacological effects of the drugs caused
sedation such as:
• small doses cause sedation,
• larger doses may bring about surgical anesthesia.
• This chapter will emphasize the concepts important in sleep and
wakefulness.
 Physiology of Sleep
• At the start of the 20th century, sleep was considered a passive process
but today sleep is considered an active process regulated by the reticular
activating system.
• Sleep is studied using related techniques:
• Electromyogram EMG that permit electronic
monitoring of the head and neck muscles
• Electro-oculogram, EOG monitors eye movements.
• After these and related studies three
states have been defined for sleep:
• Wakefulness
• Slow-wave sleep (SWS, non
rapid eye movement –NREM
sleep
• Paradoxical sleep PS, rapid
eye movement-REM sleep.
• The normal adult enters sleep through
NREM sleep.
• After approximately 90 minutes of NREM
sleep(it has 4 stages) the first REM sleep
occurs with a mean duration of about 20
minutes.
• NREM and REM sleep alternate cyclically
through the night.
• A normal young adult displays a sleep patter
of 75-80 % NREM and 20-25 % REM
sleep.
 Benefits of Sleep
• Psycological Healt
• Think clear Immune system
• Feel better Heart
• Mood memory Blood pressuer
• Less fragile

• Sleeplessness
• Fatigue Stress Temper
• Mood Memory
• Problem solving immunity
Sleep Factors
Neurotransmitter/Neuromodular
• Every neurotransmitter has been implicated in sleep or
wakefulness.
• If a neurotransmitter is involved in wakefulness, it may be
involved in initiation or maintenance of REM sleep.
• In contrast an antagonist of the neurotransmitter would be
anticipated to initiate or maintain NREM sleep.
In this section we are going to see some evidence for the
involvement of these neurotransmitters in sleep or
wakefulness.
Catecholamines
• Catecholamines would be involved in wakefulness and REM
sleep. When catecholamine concentration decreases, REM sleep
decrease.
Serotonin
• Initially serotonin was thought to be a sleep-promoting
neurotransmitter or an antiwaking agent.
• The serotonin agonist drugs cause wakefulness.
• Blocade of 5-HT2 receptors (e.g. Ritanserin) results in increase of
NREM and inhibition of REM sleep.
Histamine
• It is proposed that histamine may have an involvement in wakefulness
and REM sleep. In the CNS, histamine regulates H1, H2, H3 receptors. H1
receptor agonists and H3 receptor antagonists increase wakefulness while
H1 receptor antagonists and H3 receptor agonists have the opposite effect.

Acetylcholine
• The cholinergic system was the first neurotransmitter system shown to
have a role in wakefulness and initiation of REM sleep. Acetylcholine,
cholinergic agonists and cholinesterase inhibitors are effective in the
initiation of REM sleep from NREM sleep.
Adenosine
• Considerable evidence suggests that adenosine acts as
neurotransmitter in the mammalian nervous system. The
stimulation of the adenosine A1 receptors with adenosine
causes a hypnotic effect. Hypnotic effects occur via
suppression of calcium reflux.

• A decrease in the amount of neurotransmitter released into

the synapse in brain is associated with an increase in both
REM and NREM sleep.
GABA
GABA is the most important inhibitory transmitter of the
mammalian CNS. If GABAergic receptors are
activated by an agonist, hypnotic activity will be
observed.

Melatonin
Melatonin, referred to as the hormone of darkness, is
normally secreted during the night.
Oral administration of melatonin is associated with faster
sleep onset and increased total sleep time. But
mechanism of this event is not well understood.
Classification of Sedative-Hypnotics
The sedative-hypnotic drugs are not characterized by common
structural features.
The classification is as follows:
• Barbiturates
• Aldehydes
• Acetylene derivatives
• Acyclic hypnotics containing nitrogen
• Piperidinediones
• Benzodiazepines
•Others (Including endogenous substances and hypnotics
originated from plants.
Barbiturates
• These drugs depress neuronal activity, as well as skeletal muscle,
smooth muscle and cardiac muscle activity.

• Depending on the compound, dose and route administration, the

barbiturates can produce different degrees of depression: sedation,
hypnosis or anesthesia.
2,4,6-Trioxopirimidin (barbituric acid) was
synthesized in 1863 but this compound did not show
any pharmacological activity.
Then 5,5-diethylbarbituric acid was synthesized by
Fischer in 1903 and hypnotic activity of this compound
was shown.
Sedative-Hypnotic barbiturates in clinical use
Compounds R5’ R5 R1 Duration
of action
hour)

Barbital -C2H5 -C2H5 -H 4-12

5,5-diethylbarbituric acid
Probarbital --C2H5 -CH(CH3)2 -H 4-12
5-ethyl-5-isopropylbarbituric
acid
Butetal -C2H5 -C4H9(N) -H 4-12
5-butyl-5-ethylbarbituric acid

Phenobarbital --C2H5 -H 4-12

5-ethyl-5-phenylbarbituric
acid
 Compounds R5’ R5 R1 Duration
of action
hour)

Aprobarbital -CH2-CH=CH2 -CH(CH3)2 -H 2-8

5-allil-5-izopropylbarbituric acid
butabarbital --C2H5 CH CH2 CH3 -H 2-4
5-ethyl-5-(1- CH3
methylpropyl)barbituric acid
amobarbitral -C2H5 -CH2-CH2--CH(CH3)2 -H 2-8
5-ethyl-5-isopentylbarbituric acid

allobarbitral -CH2-CH=CH2 -CH2-CH=CH2 -H 2-8

5,5-diallilbarbituric acid
Compounds R5’ R5 R1 Duration
of action
hour)
heptabarbitral -C2H5 -H 2-4
5-ethyl-5-
cycloheptenilbarbituric acid
butalbital -CH2-CH=CH2 -CH2--CH(CH3)2- -H 2-4
5-allil-5-isobutylbarbituric acid

vinbarbitral -C2H5 -CH2--CH2--CH(CH3)2 -H 2-8

5-ethyl-5-(1-
methylbutenyl)barbituric acid

pentobarbital -CH2-CH=CH2 -CH2-CH=CH2 -H 2-8

5-ethyl-5-(1-
methylbutyl)barbituric acid
 *Synthesis of Barbituric Acid Derivatives
• Malonic acid or substitute malonic acid esters react with urea or
thiourea in the presence of a strong base to yield barbiturate or
thiobarbiturate.

• For the synthesis of N-substituted barbiturate, substituted urea is used

instead of urea.
• According to the aliphatic, cycloaliphatic or phenyl of the
substituents R1 and R2 of the barbiturates, the synthesis of
the substituted diethyl malonate is done differently.

If R1 : Aliphatic and R2 : Aliphatic, substituted malonic acid esters are

prepared as a result of the reaction of malonic acid ester against base with
alkyl halides.

1 1
H COOC2H5 R R
COOC2H5 COOC2H5
NaOC2H5 NaOC2H5
C 1 C C
2
H COOC2H5 R X R X
2
R
H COOC2H5 COOC2H5
if R1 : Aliphatic and R2 : Cycloaliphatic, the monosubstituted malonic acid ester
obtained by the reaction of malonic acid ester with cycloaliphatic ketones is treated
with alkyl halides in basic medium and appropriate disubstituted malonic acid esters
are obtained.

H COOC2H5 H COOC2H5
C + O OH C
H COOC2H5 COOC2H5

NaOC2H5 R1 COOC2H5
C
R1 X COOC2H5
If R1 : Aliphatic and R2 : Phenyl, mono-substituted malonic acid esters are obtained as a
result of first acid hydrolysis and then esterification of the product obtained from the
reaction of phenylacetonitrile with diethyl oxalate in basic medium. When
monosubstituted malonic acid esters are reacted with alkyl halides in basic medium, the
corresponding disubstituted malonic acid esters are obtained.

CN H COOH
+
COOC2H5 NaOC2H5 H3O
CH2CN + CH COOC2H5 C
COOC2H5 COOC2H5

1
+ H COOC2H5 R COOC2H5
C2H5OH / H NaOC2H5
C C
1
COOC2H5 R X COOC2H5
 Mode of Action
• At therapeutic doses the barbiturates enhance GABAergic
inhibitory response in a mechanism similar to that of the
benzodiazepines.

• At higher concentrations the barbiturates can potentiate the

GABAA-mediated chloride ion conductance and enhance both
GABA and benzodiazepine binding.
Chemical Structure and Biologic Activity
• Thousands of barbiturates have been synthesized but
no clear correlation has been found between structure
and activity.
• In 1951 a scientist made his fundamental postulation
that, in order to possess good hypnotic activity, a
barbituric acid must be a weak acid and must have a
lipid/water partition coefficient between certain
limits.
 • Structure-Activity Relationship

• Only 5,5-disubstitue barbituric acids, 5,5-thiobarbituric

acids and 1,5,5-trisubstituted barbituric acids show
hypnotic activity

• For the optimal hypnotic activity, at carbon 5, the sum of

carbon atoms of both constituents should be between 6-
10.
• As the number of carbon atoms at the fifth carbon position
increases, the lipophilic character of the substituted
barbituric acids also increases.

• Branching, unsaturation, replacement of alicyclic or

aromatic substituents for alkyl substituents and introduction
of halogen into the alkyl substituents all increase the lipid
solubility of the barbituric acid derivatives.
• Substitution on nitrogen : Substitution one amide
hydrogen by alkyl groups increases lipid solubility.
The result is a quicker onset and a shorter duration
of activity.
• Modification of oxygen: Replacement of C2
oxygen by sulfur increases lipid solubility.
Maximal thiobarbiturate brain levels are quickly
reached.
• As a result, these drugs (thiopental) are used as
intravenous anesthetics.
pKa and structure of the barbiturates, the 5,5-disubstituted barbituric acid
contains three lactam groups can undergo pH dependent lactim-lactam
tautomerisation as shown in figure.

O
1 NH
R
2 O
R NH
O

NaOH NaOH
pHa 7.1-8.1 pHa 11.7-12.7

O O
1 1 N
R N R
- -
2 O 2 O
R NH R N
O O-

Monolactim dilactim

pH dependent tautomerization of barbiturates.

5,5-Disubstituted barbituric acids are relatively weak
acids and salt of these barbiturates are easily formed by
treatment with bases.

In the alkaline media ring opening occurs, the resulting

produces are malonic acid diamide derivatives.

1
1O OH R H
R
2 2
O R NHCONH 2 R NHCONH 2
1
R NH O O
OH -/ H 2O
2 O
R NH O
1
O R NH 2
2
R NH 2
O
 Metabolism
Phenobarbital is representative of the metabolic
pathway for the barbiturates
Metabolic pathway of hexobarbital

3'-hydroxyhexobarbital 3'-ketohexobarbital
• Oxidation of substituents at carbon 5 occurs by CYP 450. The
initial products are alcohols or phenols that form glucronide
and sulfur conjugates.
• The alcohols can undergo further oxidation to ketones to
carboxylic
acids. Oxidative N-dealkylation at the nitrogen occurs by the
CYP
450. But it is not a rapid process.
• Oxidative desulphurization of 2-thiobarbiturates takes place
to yield the more hydrophilic barbiturates
 Benzodiazepines
Many compounds in the structure of 1,4-Benzodiazepine show
tranquilizing, muscle relaxant, anticonvulsant and sedative-
hypnotic effects. Although the tranquilizing effect is essential in
1,4-Benzodiazepines in practice, sedation is generally observed. It
is known that in some 1,4-benzodiazepine derivatives, the
hypnotic and antiepileptic effects increase with the contribution of
substituents.
R2
R3
9 N
8 1 2 R4
3
7
R1 5
4 H
6 N
R5

General structure of benzodiazepines

Although no apparent selectivity for hypnosis has been
determined for this group, some 1,4-benzodiazepine derivative
compounds are widely used as sedatives. These constitute a
significant reduction in REM sleep and the last two stages of
NREM sleep. Some 1,4-benzodiazepine compounds with
sedative-hypnotic effect are flurazepam, lorazepam, oxazepam,
temazepam, and triazolam.
 Aldehydes

• During 50s and 60s chloral hydrate was widely promoted as a hypnotic
because did not significantly suppress REM sleep.
• Today, it still finds use as a sedative in no operating room procedures for
the pediatric patient.
OH
Cl3C CH
OH

¨ Chloral hydrate
Trichloroacetaldehyde hydrate
The drug is readily absorbed from GIT. It is quickly
reduced trichloroethanol in the liver or by aldehyde
dehydrogenase tricholoroacetic acid metabolize occurs
Piperidinediones
• Encouraged by the success of barbiturates in sedative hypnotic
therapy, structurally related heterocyclic compounds
containing the lactam functional group were prepared and
tested for hypnotic activity.
• Of the piperidinedions, methyprylon and glutethimide
introduced in the middle 1950s, only glutethimide is still in
use for its hypnotic activity.
• Their mechanism of action resemble that of barbiturates and
they suppress REM sleep at hypnotic doses.
¨ Methyprylon
3,3-diethyl-5-methyl-2,4-piperidinedione

O CH3
C2H5
C2H5
NH
O

It significantly reduces REM sleep at his hypnotic dose.

It is extensively metabolized to oxidized metabolites
that are often further conjugation with glucronic acid.
¨ Glutethimide
3-Ethyl-3-phenylpiperidine-2,6-dione

• This drug is one of the most active non-barbiturate hypnotics that are
structurally similar to the barbiturates especially phenobarbital.
• It was concidered to be safer than the barbiturates at the hypnotic dose
in insomnia .

O
C2H5 NH
O
 The compound is prepared by the condensation reaction of 2-
phenylbutironitril and methyl acrilate or acrilonitrile (micheal
addition).

CH2CH2COOCH3 CH2CH2COOH
CH2 CH COOCH3 NaOH
C C
C2H5 CN C2H5 CONH2
H
C
C2H5 CN

CH2 CH CN CH2CH2CN H2SO4

C O
C2H5 N
C2H5 CN
O H
• Consistent with its high-lipid partition coefficient it undergoes
extensive oxidative metabolism in the liver
• The drug is used as a racemic mixture. Biotransformation in
glutathimide either from C-5 at the piperidinedione ring or by
hydroxylation of the side chain. Piperidinedione ring
hydroxylation occurs with ethyl group in the R(+) enantiomer
side chain hydroxylation in the S(-) enantiomer

• Glutethimide poisoning is more dangerous than barbiturate

poisoning.
¨ R(+) glutetimit

¨ S(-) glutetimit
 O
¨ Thalidomide
N

O O
CH3 NH
O

Thalidomide was introduced in the middle 1950s, but was

removed due to the teratogenic side effects.
The thalidomide disaster is one of the darkest episodes in
pharmaceutical research history.
The drug was marketed as a mild sleeping pill safe even for
pregnant women. However, it caused thousands of babies
worldwide to be born with malformed limbs. The damage was
revealed in 1962. Before then, every new drug was seen as
beneficial. Today it only uses for Leprea.
(RS)-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione
Ureides
• The barbiturates are basically a cyclic urea in which malonic acid is
condenced with urea.

H H Br
H3C N N CH2CH3
CH2CH3
O O O

•
Acetylcarbromal

• Although the ureides were once commonly used, only

acetylcarbromal is still available. It is metabolized to urea and is
readily eliminated in the urine. Because bromide ion is released
in vivo, prolonged use of these compounds is not
recommended because of the possible development of
bromism in patients
Antihistamines and Anticholinergics
• Some of the antihistamines (can cross the blood-brain barrier)
are used for their hypnotic activity.
• The primary antihistamines used for their sedative effect are
diphenhydramine and doxylamine which belong to the
ethonalamine class of antihistamines.
¨ Diphenhydramine
2-diphenylmethoxy-N,N-dimethylethylamine

CH3
CH O CH2 CH2 N
CH3

¨ Doxylamine
CH3
O N(CH3)2