SAR of Benzodiazepines (BZDs)

• SAR of Benzodiazepines (BZDs) highlights the importance of the 1,4-benzodiazepine nucleus for activity.
• SAR of Benzodiazepines (BZDs) shows how ring substitutions modify potency, duration, and receptor affinity.
• Benzodiazepines act primarily at the GABA-A receptor to enhance inhibitory neurotransmission.

Key SAR of Benzodiazepines (BZDs) Points:

1. Aromatic Ring at Position 5 (C-5):

   • A phenyl group at C-5 is important for activity.
   • Substitutions at ortho-positions of this phenyl ring (like Cl or F) enhance activity.
   • Para-substitution usually reduces activity.

2. Electron-Withdrawing Group at Position 7 (C-7):

   • Halogens (Cl, NO₂) increase potency.
   • Substitution at positions 6, 8, or 9 usually reduces activity.

3. Heterocyclic Ring Fusion at N-1 and C-2:

   • The 1,4-diazepine ring is essential.
   • Changes here can influence receptor binding.

4. Hydroxyl group at C-3:

   • Enhances water solubility and metabolism (e.g., Lorazepam).
   • Not always necessary but affects onset and duration.

5. N-1 Substitution:

   • Alkyl groups (e.g., methyl in Diazepam) are tolerated.
   • Bulky groups reduce activity.

6. Ring B Fusion (1,2-benzodiazepines):

   • Some analogs (triazolo- or imidazo-rings) increase potency and duration (e.g., Alprazolam).

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