SAR of Barbiturates

• SAR of Barbiturates shows activity depends on substitutions at C5 and heteroatom modifications.
• SAR of Barbiturates reveals lipophilicity increases potency, while side chains alter duration.
• Barbiturates act by enhancing GABA-A activity and directly activating the GABA-A receptor at higher doses.

Core Structure:

• Barbituric acid nucleus (pyrimidine ring with keto groups at C-2 and C-4, C-6).

Key SAR of Barbiturates Points:

1. Substitution at C-5 (R₁ and R₂ groups):

   • Essential for hypnotic/sedative activity.
   • Alkyl or aryl groups (C5 disubstitution) increase lipid solubility, leading to faster onset and shorter duration.
   • Optimal total carbon atoms in R₁ + R₂ = 6–10 for good CNS activity.

2. Unsaturation or branching in R₁/R₂:

   • Increases potency and shortens duration (e.g., thiopental).

3. Modification at N-1 or N-3:

   • Small alkyl groups are tolerated; bulky groups reduce activity.
   • N-alkylation increases lipid solubility and alters duration.

4. Oxygen at C-2 replaced with sulfur:

   • Example: Thiobarbiturates (e.g., thiopental) are more lipophilic and have faster onset.

5. C-6, C-4 substitution (with groups other than =O):

   • Typically abolishes activity.

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