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

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

Temazepam

IUPAC nomenclature

7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-1,4-benzodiazepin-2-one

Classification

Temazepam is a benzodiazepine sedative-hypnotic.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 300.74 g/mol
2 Physical appearance Solid
3 Melting point 119-121°C
4 Octanol/water partition coefficient 2.19
5 Solubility 164 mg/L
6 Presence of ring Diazepine, benzene
7 Number of chiral centers 1
 

 

Mechanism of Action

i. Temazepam binds nonspecifically with benzodiazepine receptors BNZ1.

ii. It coupled with GABAA receptors and increases the GABA affinity for the GABA receptor.

iii. This results in opening of the chloride channel and thus, causes hyperpolarization of the cell membrane which prevents further excitation of the cell.

 

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 dereases 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

i. 7-chloro-5-phenyl-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodia- zepin-2-on-4-oxide undergoes methylation of the nitrogen of the amide group in the first position of the benzodiazepine ring by using dimethylsulfate to give 1-methyl-7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on-4-oxide.

ii. The product undergoes acetylation using acetic anhydride to produce 1-methyl-3-acetoxy-7-chloro-5-phenyl-1,3-dihydro-2H-1, 4-benzodiazepin-2-one.

iii. Alkaline hydrolysis results in removal of acetyl group to give temazepam. [2]

 

Therapeutic Uses

Temazepam is used for:

  • Treatment of insomnia

 

Side Effects

Side effects of Temazepam are:

  • Dizziness
  • Memory loss
  • Hallucinations
  • Confusion
  • Mood changes
  • Anxiety
  • Aggressive behavior

 

 MCQ

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

i. Electronegative group at 7-position of the ring A A. Increase in functional anxiolytic activity
ii. Substitutions at 6, 8 or 9 position with electronegative group on ring A B. Decreases the functional anxiolytic activity
iii. When Heterocycles used as ring A C. maximum activity is observed
iv. When the proton accepting group is present on the 2-position of the ring B D. Poor pharmacological activity

 a) i-D, ii-C, iii-A, iv-B

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

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

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

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

  • Temazepam: 5-butan-2-yl-5-ethyl-1,3-diazinane-2,4,6-trione
  • Diazepam: 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]- 4,5-dihydro-1H-imidazole
  • Norepinephrine: (R)-4-(2-amino-1-hydroxyethyl)benzene-1,2-diol
  • Epinephrine: (R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-1,2-diol

a) TFTF

b) TTFF

c) FTTF

d) FFTT

Q.3 Physical appearance of Temazepam is?

a) Red-brown crystalline powder

b) Solid

c) Green granular form

d) None of these

Q.4 Temazepam shows its mechanism of action through biding with which receptor?

a) BNZ1

b) Pain receptors

c) Light receptor

d) None of the above

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

a) Sedative before surgery

b) Treatment of Insomnia

c) Treatment of cancer

d) All of the above

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

I. Temazepam: Barbiturate sedative-hypnotic

II. Loxapenes: Benzazepenes

III. Thiothixene: Benzodiazepenes

IV. Haloperidole: Butyrophenone

a) I

b) I, III

c) II, IV

d) II, III 

Q.7 Type of ring present in the structure of temazepam?

a) Diazepine

b) Triazole

c) Pyrimidine

d) Both a) and c)

 

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ANSWERS

1-d

2-d

3-b

4-a

5-b

6-c

7-d

 

REFERENCES

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

[2] Vardanyan R, Hruby V. Synthesis of essential drugs. Elsevier; 2006 Mar 10.

 

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