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

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

Midazolam

IUPAC nomenclature

8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Classification

Midazolam is a benzodiazepine sedative-hypnotic.

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 325.8 g/mol
2 Physical appearance White to light yellow crystalline solid
3 Melting point 159°C
4 Octanol/water partition coefficient Log Kow=4.33
5 Solubility 1.34X10-1 mg/L in water
6 Presence of ring Present
7 Number of chiral centers Not present
 

Mechanism of Action

The sedation effect, relaxing of skeletal muscles, inducing of sleep, anesthesia and amnesia properties of drug is due to the increase in activity of GABA by the drug. Midazolam binds with GABAA receptors and potentiates the effects of GABA by increasing the frequency of chloride channel opening and hyperpolarization.

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. [1]

Method of synthesis

(2-amino-5-chlorophenyl)(2-fluorophenyl)methanone and N-(3-amino-2-oxopropyl)acetamide undergoes a ring forming reaction in the presence of a catalyst to give midazolam.     [2]

 

Therapeutic Uses

Midazolam is used for:

  • Inducing drowsiness in children
  • Treatment of anxiety
  • Causing forgetfulness of the surgery

 

Side Effects

Side effects of Midazolam are:

  • Dizziness
  • Nausea
  • Vomiting
  • Mood changes
  • Aggressive behavior
  • Tremors
  • Irregular heartbeats
  • Blurred vision
  • Allergic reaction
  • Trouble breathing

 

MCQ

 Q.1 Match the following with correct SAR of the drug Midazolam-

i. An electronegative group at 7-position of the ring A A. Increases the functional anxiolytic activity
ii. Substitutions at 6, 8 or 9 position with electronegative group on ring A B. Decreases the functional anxiolytic activity
  C. Decrease the functional anxiolytic activity
  D. Increase the functional anxiolytic activity

 a) i-A, ii-D

b) i-A, ii-C

c) i-B, ii-C

d) i-B, ii-D

Q.2 Correct sequence for the True/False for correct IUPAC names of the drug can be?

  • Benztropin: (3-endo)-3-(Diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]octane
  • Fesoterodine: [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate
  • Flurazepam: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
  • Midazolam: 7-Chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one

a) TFTF

b) TTFF

c) FFTT

d) TTFT

Q.3 Number of chiral carbons present in the structure of Midazolam?

a) 0

b) 1

c) 2

d) 3

Q.4 Midazolam drug shows its action through??

a) Agonizing the acetylcholine receptors

b) Antagonizing the muscarinic receptors

c) Binding with GABAA receptors

d) ß-inhibition

Q.5 Which amongst the following is a therapeutic use of drug Midazolam?

a) Inducing drowsiness in children

b) Treatment of Alzhiemer’s disease

c) Treatment of Overactive bladder

d) Treatment of Asthma

Q.6 Which of the following drug and their classification are correct?

I. Benztropin: acetylcholine antagonist

II. Fesoterodine: Nitrogen mustard

III. Flurazepam: benzodiazepine sedative hypnotic

IV. Midazolam: Acetylcholine Nicotinic receptor antagonist

a) I, III

b) I, III, IV

c) II, IV

d) I, II, III, IV 

Q.7 (2-amino-5-chlorophenyl)(2-fluorophenyl)methanone and N-(3-amino-2-oxopropyl)acetamide undergoes a ring forming reaction in the presence of a catalyst to give which drug?

a) Fesoterodine

b) Midazolam

c) Fludarabine

d) Methotrexate

 

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ANSWERS

1-a

2-b

3-a

4-c

5-a

6-a

7-b

 

 

REFERENCES

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

[2] Huber JE, inventor; Pharmacia, Upjohn Co Inc, assignee. Process to produce midazolam. United States patent US 5,831,089. 1998 Nov 3.

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