Diazepam

• Diazepam treats anxiety, seizures, muscle spasms, and alcohol withdrawal effectively.
• Diazepam enhances GABA action, producing sedative, anxiolytic, and anticonvulsant effects.

Chemical Formula:

• C₁₆H₁₃ClN₂O

Mechanism:

• Enhances GABAergic transmission at GABA-A receptors by increasing frequency of Cl⁻ channel opening

Uses:

• Anxiety
• Muscle spasms
• Seizures (status epilepticus)
• Alcohol withdrawal
• Premedication for procedures

Side Effects:

• Drowsiness, sedation
• Amnesia
• Muscle relaxation
• Risk of tolerance and dependence
• Respiratory depression (IV, or with CNS depressants)

SAR of Diazepam:

1. 1,4-benzodiazepine ring:

   • Essential for activity.
   • 7-membered diazepine ring fused to a benzene ring is critical.

2. Electron-withdrawing group at position 7 (e.g., Cl, NO₂):

   • Enhances binding to GABA_A receptor.
   • 7-chloro increases potency and lipophilicity.

3. Phenyl ring at position 5:

   • Required for activity.
   • Substitutions on this ring can influence potency and receptor selectivity.

4. N1 substitution (e.g., methyl):

   • Affects pharmacokinetics, potency, and duration of action.

5. Position 2-keto group:

   • Essential for binding; participates in hydrogen bonding at the receptor.

6. Lipophilicity:

   • Increases CNS penetration and onset of action.

General Synthesis of Diazepam:

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