CLOBAZAM Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

CLOBAZAM Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

Clobazam

IUPAC nomenclature

7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione.

Classification

Clobazam is a benzodiazepine sedative-hypnotic.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 300.74 g/mol
2 Physical appearance White to almost white crystalline powder
3 Melting point 166-168°C
4 Octanol/water partition coefficient 2.12
5 Solubility 188 mg/L in water
6 Presence of ring Diazepine, benzene
7 Number of chiral centers Not present
 

 

Mechanism of Action

i. Clobazam binds at distinct binding sites associated with the chloride ionopore present at the post synaptic GABA receptor.

ii. Clobazam increases the opening duration of the chloride ionopore.

iii. This results in increase in the inhibitory effect of GABA through hyperpolarization and stabilization of membrane. [1]

 

Structure Activity Relationship

  • Ring A should include an aromatic or heteroaromatic ring for binding with 5-phenyl-1,4-benzodiazepin-2-one derivatives.
  • An electronegative group at 7-position of the ring A increases the functional anxiolytic activity.
  • Substitutions at 6, 8 or 9 position with electronegative group on ring A will decrease the functional anxiolytic activity.
  • When Heterocycles used as ring A, drug shows poor pharmacological activity.
  • A proton-accepting group is essential on Ring B for binding with GABAA
  • When the proton accepting group is present on the 2-position of the ring B, and is in coplanar spatial orientation with Ring A, maximum activity is observed.
  • Replacement of oxygen with sulfur in ring B results in alteration in the selectivity for binding with GABA BZR subpopulations, but anxiolytic properties are maintained.
  • There is no effect on agonist activity, but the antagonist activity decreases when methylene 3-position or imine nitrogen of the ring B is substituted.
  • Derivatives having the 3-hydroxy moiety are fast excreted.
  • Sterically large substituents on ring B, like tert-butyl group reduces the receptor affinity and the in vivo activity.
  • 4,5-double bond and 4-position nitrogen is not essential for anxiolystic activity.
  • BZR affinity is decreased if C=N bond is replaced with C-N bond.
  • 5-phenyl ring C is not necessary for the binding with BZR.
  • Substitution at the para position of the ring C decreases the agonist activity of the drug.
  • There is no change observed in the agonist property of the drug when there is substitution at ortho position.
  • When 1,2-bond f the ring C is annelated with an additional electron rich ring such as imidazole, affinity of the BZR increases. [2]

 

Method of synthesis

i. 5-chloro-2-nitro-Nphenylaniline is reacted with mono alkyl malonate to produce corresponding alkyl 3-((5-chloro2-nitrophenyl) (phenyl)amino)-3-oxopropanoate.

ii. This on reduction produces diamine compound.

iii. Cyclization of alkyl 3-((2-amino-5- chlorophenyl) (phenyl) amino)-3-oxopropanoate in acid medium produces 8-chloro- 1-phenyllH-benzo[b][l,4]diazepine-2,4(3H,5H)-dione.

iv. Reaction of the above formed compound with methylhalide produces clobazam.

 

Therapeutic Uses

Clobazam is used for:

  • Treatment of seizures

 

Side Effects

Side effects of clobazam are:

  • Dizziness
  • Drowsiness
  • Trouble sleeping
  • Constipation
  • Drooling
  • Fatigue
  • Cough
  • Fever
  • Depression
  • Suicidal thoughts
  • Mood changes
  • Painful urination
  • Nervousness
  • Slurred speech

 

 MCQ

Q.1 ‘7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione’ is the IUPAC nomenclature of which drug?

a) Clobazam

b) Diazepam

c) Triazolam

d) Mephobarbital

Q.2 Molecular weight of Clobazam?

a) 281.27 gm/mol

b) 300.74 gm/mol

c) 553.78 gm/mol

d) 109.33 gm/mol

Q.3 Match the following with correct classifications of the drugs?

i. Clobazam A. Benzodiazepine
ii. Clozapine B. Butyrophenone class
iii. Zolpidem C. Benzapene
iv. Pimozide D. Nonbenzodiazepine agonist

 a) i-A, ii-C, iii-D, iv-B

b) i-C, ii-A, iii-D, iv-B

c) i-D, ii-A, iii-B, iv-C

d) i-B, ii-D, iii-A, iv-C

Q.4 Correct steps for the mechanism of action of the drug Clobazam

I. Hyperpolarization and stabilization of membrane

II. Increase in duration of chloride ionopore opening

III. Binding with GABA receptors

a) I – III – II

b) I – II – III

c) III – II – I

d) II – I – III

Q.5   Correct sequence for True and False for the given statements related with the SAR of drug clobazam?

  • An electronegative group at 7-position of the ring A decreases the functional anxiolytic activity.
  • Substitutions at 6, 8 or 9 position with electronegative group on ring A will Increases the functional anxiolytic activity.
  • When Heterocycles used as ring A, drug shows poor pharmacological activity.
  • A proton-accepting group is essential on Ring B for binding with GABAA

a) TFTF

b) FFTT

c)FTFF

d) FFTF

Q.6 Number of chiral centers present in Clobazam is?

a) 1

b) 2

c) 3

d) 0 

Q.7 The drug clobazam is mainly used for?

a) Treatment of Seizures

b) Treatment of dizziness

c) Treatment of drooling

d) All of the above 

 

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ANSWERS

1-a

2-b

3-a

4-c

5-b

6-d

7-a

 

REFERENCES

[1] Sankar R. GABA A receptor physiology and its relationship to the mechanism of action of the 1, 5-benzodiazepine clobazam. CNS drugs. 2012 Mar 1;26(3):229-44.

[2] Lemke TL, Zito SW, Roche VF, Williams DA. Essentials of Foye’s principles of medicinal chemistry. Wolters Kluwer; 2017, 473-474.

 

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