MEDICINAL

CHEMISTRY OF
SEDATIVES HYPNOTICS
BY INAYATULLAH
ROLL NO. 36
INTRODUCTION

Nervous
system

central
peripheral
nervous
nervous
system
system
STATES OF THE BRAIN:
• Sleep ,wakefulness ,extreme excitement ,in different levels
of mood ,(exhilaration ,depression ,fear)
• These all states result from;
i. Activating
ii. Inhibiting
forces being generated by the brain.
CNS AGENTS USED;

• Based on the above discussion two types of CNS agents are used;
i. CNS stimulants
ii. CNS depressants
Sedative hypnotics are major CNS depressants;
SEDATIVES AND HYPNOTICS:

Sedatives:
• Sedatives are central nervous system (CNS) depressant drugs that
reduce excitement, anxiety, and produce relaxation and calming
effect.
Hypnotics:
• Hypnotics are drugs that depress the CNS and produce sleep
similar to that of natural sleep.
CLASSIFICATION:
• Sedatives and hypnotics are classified on the basis of their chemical
structure, as follows:
• 1. Barbiturates
• 2. Benzodiazepines
• 3. Acyclic hypnotics containing nitrogen
• 4. Cyclic hypnotics containing nitrogen
• 5. Alcohols and aldehydes
• 6. Acetylene derivatives Drugs
• 7. Miscellaneous
• a. Inorganic salts
• b. Acids and esters
• c. Antihistaminic and anticholinergic agents
• d. Other opioids: morphine, pethidine
• e. Neuroleptics: chlorpromazine, triflupromazine
• f. Melatonin receptor antagonist: Ramelteon
• 8. Newer agents (Non benzodiazepines)
• Zolpidem ,zaleplon ,Eszopiclone.
BENZODIAZEPINES:
• Benzodiazepines potentiate the binding of GABA .
• Benzodiazepines modulate the functions of GABA A receptors leading to
neuronal hyperpolarization and various CNS effects e .g .(depression
,anxiolytic effects ,muscle relaxation ,convulsions and etc.)
• Binding site is well characterized and found at the interface of the alpha and
gamma subunits .
• Benzodiazepines lack any activity without GABA.
• Those Benzodiazepines which are rapidly absorbed and have high lipid
solubility and no active metabolites are useful HYPNOTICS.
• Those Benzodiazepines which are slowly absorbed and have low lipid
solubility and few or no active metabolites are useful ANXIOLYTICS.
DEVELOPMENT OF BENZODIAZEPINES:

• Chlordiazepoxide (Librium) is the first Benzodiazepines to be marketed for clinical

use in 1960s.
• structural modification in Chlordiazepoxide to enhance its pharmaceutical
elegance lead to the development of DIAZEPAM (Valium) in 1959 and was
marketed in 1963.
• And subsequently thousands of benzodiazepines were synthesized and more than
two dozens are currently in market.
• In 1981 a great breakthrough took place that was the development of Flumazenil
(a drug that blocks the pharmacological effects of benzodiazepines.)
MECHANISM OF ACTION:

• Benzodiazepines bind to Benzodiazepine binding site at GABA A receptors

,and potentiate the binding of GABA(major inhibitory neurotransmitter) to
GABA A receptors leading to neuronal hyperpolarization which facilitates an
increase in firing threshold potential and reduces the chances of production
of action potential and various CNS effects e .g .(depression ,anxiolytic
effects ,muscle relaxation ,convulsions and etc.)
INDICATIONS OF SEDATIVES HYPNOTICS /
USES:
• Sedatives and hypnotics
• Anxiolytics
• Anticonvulsants
• Muscle relaxants
• General anesthetics
• Preanesthetic medication
• Anti psychiatrics
• To potentiate effects of analgesic drugs
• Adjuvant to anesthesia
CLASSIFICATION OF BENZODIAZEPINES:
Diazepam
Oxazepam
Chlordesmethyl diazepam
Fosazepam
Prazepam
Nitrazepam
Nordiazepam
Quazepam
Halozepam
Temazepam
Lorazepam
Clonazepam
Triazolo benzodiazepines
Alprazolam
Triazolam
Estazolam
PHARMACOPHORE STRUCTURE OF
BENZODIAZEPINES:
• Name R1 R2 R3 R7 R2′
• Diazepam –CH3 =O –H –Cl –H
• Oxazepam –H =O –OH –Cl –H
• diazepam –H =O –H –Cl –Cl
• Quazepam –CH2CF3 =S –H –Cl –F
• Name R1 R2 R3 R7 R2′
• Halozepam –CH2CF3 =O –H –Cl –H
• Temazepam –CH3 =O –OH –Cl –H
• Nitrazepam –H =O –H –NO2 –H
• Nordiazepam –H =O –H –Cl –H
• Nimetazepam –CH3 =O –H –NO2 –H
• Name R1 R2 R3 R7 R2′
• Nimetazepam –CH3 =O –H –NO2 –H
• Flunitrazepam –CH3 =O –H –NO2 –F
• Flurazepam –(CH2)2N (C2H5)2 =O –H –Cl –F
• Lorazepam –H =O –OH –Cl –Cl
• Clonazepam –H =O –H –NO2 –Cl
• Doxefazepam –CH2OH =O –OH –Cl –F
SAR OF BENZODIAZEPINES:
RING A: AROMATIC OR HETEROAROMATIC
:
• It is the minimum requirement for binding to benzodiazepine receptor.
• It is believed to participate in pi-pi stacking with aromatic amino acid residue of the
receptor.
• Substitution on ring A has varied effects on binding of benzodiazepine to receptor.
• An electronegative group (halogens ,nitro group) Substituted at 7th position markedly
increases its activity.
• On the other hand substitution at 6th ,8th or 9th generally decreases activity.
• If ring A is replaced by heterocyclic compound that generally imparts low binding affinity
and reduced pharmacological effects.
RING B:
• The optimal activity occurs when the proton accepting group in the 2nd position of ring B (e . g
.) the carbonyl moiety is in coplanar spatial orientation with the ring A.
• A proton accepting group is required for interaction with histidine residue that serves as a
proton source in GABA A alpha 1 subunit.
• Substitution of Sulphur for the oxygen at second position as in Quazepam may effect
selectivity for bonding to benzodiazepine receptor.
• When substituted at position 3 by hydroxyl group that increases polarity hence have
comparable potency and excreted faster and imparts shorter duration of action . e .g.(LOT)
• N-1 amide can be unsubstituted or substituted with alkyl ,alkylamine fused into electron rich
triazole ring system (e .g .alprazolam ,midazolam ,triazolam)which contributes to higher
affinity for the receptor
• The triazole derivatives present oxidative metabolism that prolongs the duration of action.
RING C :

• The 5-phenyl or ring C is not required for binding to benzodiazepine receptor

in vitro.
• It may contribute favorable hydrophobic or steric interactions to receptor
binding.
• Can be substituted or unsubstituted with halogen in the ortho position which
imparts activity whereas substitution at para position imparts inactivity.
•
SIDE EFFECTS:

• Dependence.
• Tolerance .
• Increases the incidence of nightmares ,Irritability ,tachycardia
,sweating ,hallucinations ,restlessness ,euphoria ,sleep walking
,sleep talking ,confusion ,suicidal attempt ideas .
• Allergic reactions , hepatotoxicity ,hematologic reactions may
occur but the incidence is very low.
•Thank you