The document discusses various classes of sedative and hypnotic drugs including barbiturates, benzodiazepines, and newer non-benzodiazepine drugs. It describes the mechanism of action of these drugs as potentiating the effects of the inhibitory neurotransmitter GABA in the brain through binding to GABAA receptors or barbiturate sites. This results in increased chloride conductance, membrane hyperpolarization, and central nervous system depression. The document also provides structure-activity relationships and examples of specific drugs from each class like diazepam, zolpidem, and pentobarbital along with their medical uses, side effects, and synthesis when relevant.

1. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 1 | P a g e
• The drugs that act on the central nervous system (CNS) influence the lives of everyone at all times. These
drugs can selectively relieve pain, reduce fever, suppress disordered movement, induce sleep or
arousal, and reduce the desire to eat or ally the tendency to vomit. Selectively, acting drugs can be used
to treat anxiety, mania, depression, or schizophrenia and do so without altering consciousness.
• The electrophysiological signs of action in the CNS falls into two categories (i) excitatory (produce
depolarization) and (ii) inhibitory (produces hyperpolarization) in the neurons.
Sedative
❖ Sedatives are central nervous system (CNS) depressant drugs that reduce excitement, tension, and
produce relaxation.
❖ A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may
be produced. Sedation refers to decreased responsiveness to any level of stimulation; is associated with
some decrease in motor activity and ideation.
Hypnotic
❖ Hypnotics are drugs that depress the CNS and produce sleep like that of natural sleep.
Difference b/w Sedatives and hypnotics
✓ Sedatives are drugs that decreases activity and have a calming, relaxing effect. Peoples use these drugs
mainly to reduce anxiety. At higher doses, sedatives usually cause sleep. Drugs used mainly to cause
sleep are called Hypnotics.
✓ The difference between sedative and hypnotic is usually the amount of the dose- At lower dose have a
calming effect and higher doses cause sleep.
✓ At lower dose, the drug may act as sedative, while at a higher dose the same drug may act as hypnotic
Sedatives and hypnotics are also used as the following:
✓ Antianxiety Agents
✓ Anticonvulsants
✓ Muscle Relaxants
✓ General Anaesthetics
✓ Preanaesthetic Medication
✓ Antipsychiatrics
✓ To Potentiate Analgesic Drugs
✓ Adjuvant to Anaesthesia

2. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 2 | P a g e
✓ A co-drug in the Treatment of Hypertension
Different effect of HYPNOTICS of different doses
Lower dose high dose very higher dose
Sedative general anaesthetic respiratory depression
Coma
Death
CLASSIFICATION OF SEDATIVES AND HYPNOTICS
Barbiturates Benzodiazepines newer non-BZD’S Miscellaneous
Long-acting
barbiturates
✓ Barbital
✓ Phenobarbital
✓ Mephobarbital
✓ Metharbital
Short-acting
barbiturates
✓ Butobarbital
✓ Pentobarbital
✓ Secobarbital
✓ Amobarbital
✓ Cyclobarbital
✓ Heptabarbital
Ultra short-acting
barbiturates (15 min)
✓ Thiopentone
✓ methohexitone
Hypnotics
✓ Diazepam
✓ Flurazepam
✓ Nitrazepam
✓ Alprazolam
✓ Triazolam
Anti-anxiety
✓ Diazepam
✓ Chlordiazepoxide
✓ Oxazepam
✓ Lorazepam
✓ Alprazolam
Anti-convulsant
✓ Diazepam
✓ Lorazepam
✓ Clonazepam
✓ clobazam
Also known as
Z-Drugs
✓ Zopiclone
✓ Zolpidem
✓ Zaleplon
Amide & imides
✓ Glutethmide
Alcohol & their
carbamate derivatives
✓ Meprobomate
✓ Ethchlorvynol
Aldehyde & their
derivatives
✓ Triclofos sodium
✓ Paraldehyde

3. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 3 | P a g e
Benzodiazepines (BZD)
Chemistry of BZD
✓ All the BZD’s have a benzene ring (Blue color) attached to a diazepine ring (red color).
✓ BZD have a cyclic structure that includes one benzene ring with a heterocycle ring where 2 atoms are
“Nitrogen” (Diazepine), Normally in 1 & 4th
position, but which can also be in 1,5th
and 2, 3rd
position.
✓ Normally BZD used in clinically that are 1,4-dinitrogenated system.
SAR of Benzodiazepines
OR
Possibilities of Modification at
Ring A, Ring B and Ring C
1. RING-A

4. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 4 | P a g e
• The minimum requirement for 5-phenyl-1,4-benzodiaipin-2-one derivatives to BZD include an
aromatic or hetero aromatic ring.
• An electronegative group (halo or nitro) substituted at R1 position markedly increase activity and
binding affinity
• Substitution on 6,8 and 9 decrease the activity.
• Replacement of ring A with heterocyclic ring have weak activity and affinity as compared to phenyl
derivatives.
RING-B
• Alkyl substitution at R2 position will increases the activity.
• A proton accepting group C=O (carbonyl oxygen) at 2nd
position of ring B is necessary to interact
with receptor binding site.
• Substitution at 3rd
position methylene or imine nitrogen is sterically unstable.
• Substitution at 3rd
position with hydroxy moiety have comparable potency to CH analogue but are
excreted faster.
• Phenyl substitution at 5th
position increases the activity.
RING-C
• Replacement of Ring C with aromatic heterocyclic ring increases the anxietolytic activity.
• Substitution at R3 position with Halogen, increases the activity.
• Substitution at 4’ position is unfavourable for activity.
Mechanism of action
BZD
Bind to modulatory site on GABAA
Potentiate the inhibitory effect of GABA
Increases the frequency of Cl-
channel opening
Increases in chloride conductance
Membrane hyperpolarization
CNS depression

5. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 5 | P a g e
OR
Benzodiazepine receptors are present in the brain and they form a part of GABAA receptor’s chloride ion
channel macromolecular complex. Binding of benzodiazepines to these receptors produces activation of
GABAA receptor and increases chloride conductance by increasing the frequency of opening chloride ion
channel. These in turn inhibit neuronal activity by hyper-polarization and de-polarization block.
Action Clinical Use
Anxiolytic Anxiety and panic/phobias, alcohol withdrawal symptoms
Hypnotic Insomnia
Muscle relaxant Muscle spasms, spasticity caused by CNS pathologies
Anticonvulsive Attacks caused by drug intoxications, some forms of epilepsy
Amnesic Perioperative or pre-surgery medication
Side effects of BZD’s: -
Common side effects drowsiness, confusion, blurred vision
With other chronic use cause symptoms like tremors, insomnia, restlessness
Occasionally: dizziness, headache, depression, confusion, dysphasia.
Diazepam
Uses: skeletal muscle relaxant, anticonvulsant and antianxiety agent.
Side effect: drowsiness, sedation, muscle weakness.

6. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 6 | P a g e
Synthesis of diazepam:

7. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 7 | P a g e
Zolpidem: (all non-BZD’s drugs having same action as zolpidem) (“Z”-drugs)
• Less hangover effect than BZD’s
• Can given orally and well observed metabolized in liver & excreted by urine
• Having short duration of action mostly used for short-term insomnia
• Less tolerance and dependence
MOA:
Zolpidem
Binds to selectively to BZD receptors
GABA mediated neuronal inhibition
CNS depression

8. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 8 | P a g e
BARBITURATES
• Barbiturates are derivatives of barbituric acid. Their hypnotic activity is conferred by the replacement of
H-atom attached to the C-5 position by aryl or alkyl radicals.
• The barbiturates were used extensively as sedative–hypnotic drugs.
SAR of Barbiturates
The acidity value within certain limits, gives proper ratio of ionized forms that leads to cross the Blood
Brain Barrier (BBB).
Based on acidity value, divided into 2 classes
Active class Inactive class
1. 5,5’-disubstituted barbituric acid
2. 5,5’-disubstituted Thio barbituric acid
3. 1,5,5’-trisubstituted barbituric acid
1. 1-substituted barbituric acid
2. 5-substituted barbituric acid
3. 1,3-disubstituted barbituric acid
4. 1,5-disubstituted barbituric acid
5. 1,3,5,5’-tetrasubstituted barbituric acid
Substitution at C-5 (R2, R3) position should be alkyl chain length is 6-10 carbon to attain optimal activity.
Substitution at R2, R3 position with branched chain shows greater lipid solubility and hypnotic activity but
has shorter duration of action.
The greater branching shows more potent will be the drug. eg.: - pentobarbitone
Alicyclic or aromatic substituted analogue are more potent than aliphatic substituted analogue with the
same number of carbon atom.
Substitution at C-5 position shows the higher potency.
Replacement of Oxygen atom by Sulphur atom at C-4 and C-6 position, reduce the hypnotic activity.
Replacement of Oxygen atom by Sulphur atom at C-2 position leads to rapid onset of action and shorter
duration of action.

9. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 9 | P a g e
Drug R1 R2 R3
Barbital H C2H5 C2H5
Phenobarbital H C2H5
Mephobarbital CH3 C2H5
Amobarbital H C2H5
Butabarbital H C2H5
Pentobarbital H C2H5
Secobarbital H CH2=CH-CH-
Mechanism of action
Barbiturates
Bind to other modulatory site (barbiturate site)
on GABAA
Potentiate the inhibitory effect of GABA
Increases the frequency of Cl-
channel opening
Increases in chloride conductance
Membrane hyperpolarization
CNS depression

10. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 10 | P a g e
Barbiturates do not bind to benzodiazepine receptor promptly, but it binds to another site on the same
macromolecular complex to exert the GABAergic facilitator actions. The barbiturate site appears to be located
on α and β subunit. At high concentrations, barbiturates directly increase Cl– conductance and cause CNS
depression.
Barbital
Synthesis
Therapeutic uses
Sedative and hypnotics
Pre operative sedation
Treatment of seizure
Anticonvulsants
Side effects

11. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 11 | P a g e
Miscellaneous:
1. Glutethmide
It is used as a hypnotic drug to induce sleep without depressing respiration.
2. Meprobomate
It is used in the anxiety disorder and centrally action skeletal muscle relaxant.
3. Ethchlorvynol
Used for short-term hypnotic therapy in the management of insomnia
the exact mechanism of action is unknown, ethchlorvynol appears to depress the central nervous system in a
manner similar to that of barbiturates
4. Triclofos sodium
Used as hypnotics

12. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 12 | P a g e
5. Paraldehyde
Paraldehyde was used historically as a sedative and hypnotic 1. It has been used in the treatment of seizures
as an anticonvulsant
Paraldehyde is believed to reduce the release of acetylcholine in response to neuronal depolarization 3. The
exact mechanism of this effect is unknown.