notes according to the PCI syllabus

1. DRUGS ACTING ON CENTRAL
NERVOUS SYSTEM
A. Sedatives and hypnotics By
Dr.Ch.Prasad

2.  Sedatives are CNS depressants drugs that reduce
excitement and tension and produce calmness and
relaxation .
 Hypnotics are the drugs that produce the sleep similar
to the natural sleep
Both sedative and hypnotic actions may reside in the
same drug; a small dose may act as sedative,
whereas a large dose of the same drug may act as
hypnotic

3. Benzodiazepines
SAR

4. 1. Most benzodiazepines are 5-aryl-1,4-benzodiazepines and contain a
carboxamide group in the seven-membered diazepine ring structure
2. Aromatic or heteroaromatic ring A is required for the activity that may
participate in - stacking with aromatic amino acid residues of the receptor
3. An electronegative substituent at position 7 is required for activity, and
the more electronegative it is, the higher the activity
4. Positions 6, 8, and 9 should not be substituted
5. A phenyl ring C at position 5 promotes activity. If this phenyl group is
ortho (2) or diortho (2,6) substituted with electron-withdrawing
groups, activity is increased. On the other hand, para substitution
decreases activity greatly
6. In diazepine ring B, saturation of the 4,5-double bond or a shift of it to
the 3,4-position decreases activity

5. 7. Alkyl substitution at the 3-position decreases activity; substitution with a 3-
hydroxyl does not.
8. The presence or absence of the 3-hydroxyl group is important
pharmacokinetically. Compounds without the 3-hydroxyl group are nonpolar , 3-
hydroxylated in liver slowly to active 3-hydroxyl metabolites, and have long
overall half-lives.
9.In contrast, 3-hydroxyl compounds are much more polar, rapidly
converted to inactive 3-glucuronides, which are excreted in urine and thus are
short-lived.
10. The 2-carbonyl function is important for activity, as is the nitrogen
atom at position 1. The N1-alkyl side chains are tolerated.
11. A proton-accepting group at C2 is required and may interact with histidine
residue (as a proton donor) in benzodiazepine binding
site of GABAA receptor.
12. Other triazole or imidazole rings capable of H-bonding can be fused on
positions 1 and 2 and increase the activity.

6. 13. These compounds are short acting because they are metabolized rapidly by
-hydroxylation of the methyl substituent on the triazolo or imidazolo ring.

12.  Benzodiazepine receptors are present in the brain and
they form a part of a GABA-A receptor chloride ion
channel macromolecular complex. Binding of
benzodiazepines to these receptors activates GABA-A
receptor and increases the chloride ion conductance
by increasing the frequency of opening of chloride ion
channel. These in turn inhibit the neuronal activity by
hyperpolarization and depolarization block.

13.  Uses of benzodiaepines
Benzodiaepines are indicated for the symptomatic
relief of tension and anxiety ,acute alcohol
withdrawal ,adjunct theraphy in skeletal muscle
spasms, neurosis , psychoneurosis and
management of status epilepticus.

17. MODE OF ACTION
 Barbiturates bind to an allosteric recognition site on
GABAA receptors that positively modulates the effect
of the GABAA receptor—GABA binding. Unlike
benzodiazepines, they bind at different binding sites
and appear to increase the duration of the GABA-
gated chloride channel openings.
 In high doses, barbiturates can also increase
chloride ion flux without GABA attaching to its
receptor site on GABA-A. This has been termed a
GABA mimetic effect. It is thought to be related to the
profound CNS depression that barbiturates can
produce.
 GABAA receptor activation increase the membarane
permeability to chloride ion that produces
hyperpolarization in the cell body. This will inhibit the
neuronal activity.

18. SAR
 The barbituric acid is 2,4,6-trioxohexahydropyrimidine, which lacks
CNS depressant activity. However, the replacement of both hydrogens
at position 5 with alkyl or aryl groups confers the activity.
 Both hydrogen atoms at the 5-position of barbituric acid must be
replaced.

19.  This may be because if one hydrogen is available at position 5,
tautomerization to a highly acidic trihydroxypyrimidine (pKa 4)
can occur. Consequently, the compound is largely in the anionic
form at physiological pH, with little nonionic lipid-soluble
compound available to cross the blood-brain barrier.
 Sedative and hypnotic activity increases with lipid solubility until
the total number of carbon atoms of both the substituents at C-5
is between 6 and 10. further increase in the sum of the carbon
atoms decreases the activity in spite of further increase in the
lipid solubility, indicating that the lipid solubilty must remain within
the limit.
 Within the same series, the branched chain isomer has greater
lipid solubility and activity and shorter duration of action than the
straight chain isomer.
 Within the same series unsaturated derivates are more active
than corresponding saturated analogues

20.  Conversion of 5,5-disubstituted barbituric acid by methylation to a
1,5,5-trisubstituted barbituric acid does not change the activity in
significant manner.
 Introduction of polar substituent(NH2 ,RNH,OH,
COOH,SO3H)into aromatic group at C-5 decreases the lipid
solubility and potency
 Replacement of oxygen at C-2 by a sulphur atom increases quick
onset and shortens the duration of action.
Uses of barbiturates
At low doses, barbiurates are indicated for the relief of anxiety and
tension
At high doses, they are used for management of
insomnia(sleeplessness)
Long duration of action of barbiturates are also used as
anticonvulsant agents

21.  Synthesis of barbital

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