Structure-Activity Relationship (SAR) of H₁ Receptor Antagonist Antihistamines

This article explains about Diphenhydramine Hydrochloride its uses as an antihistamine for allergy relief motion sickness and sleep aid.

• The SAR of H₁ receptor antagonists outlines how their chemical structures influence their ability to block H₁ histamine receptors.
• Key structural components include aromatic substitutions, the linker atom (X), the alkyl chain, and the terminal nitrogen atom.

Basic Structure of Antihistamines

• Aryl Groups: Two aromatic rings are essential.
• Linker Atom (X): Can be Oxygen (O), Carbon (C), or Nitrogen (N).
• Ethylene Bridge: A two-carbon spacer connecting the aryl groups to the amino group.
• Amino Group: Critical for receptor binding.

1. Substitution on Aryl Groups

• Diary Substitution:

  • Essential for Activity: Present in both first and second-generation antihistamines.
  • Co-Planarity: Optimal activity requires the two aryl groups to be co-planar.

• Active Substituents:

  • Ar Groups: Phenyl and heteroaryl (e.g., 2-pyridyl).
  • Ar₁ Groups: Aryl or aryl methyl.
  • Enhancing Substituents: Chlorine (Cl), Bromine (Br), and Methoxy (O-CH₃) groups increase activity.

2. Nature of the Linker Atom (X)

• Common Substitutions: Oxygen (O), Nitrogen (N), Carbon (C).
• Active Linkers:

• • X = Oxygen: Forms amino alkyl ether analogues.
  • X = Nitrogen: Creates ethylene-diamine derivatives, introducing chirality for stereoselective binding.
  • X = Carbon: Results in mono amino propyl analogues, maintaining structural integrity.

• Inactive Substitutions: Substituting X with elements other than O, N, or C reduces or abolishes activity.

3. Alkyl Chain

• Ethylene Chain: Essential for activity, providing necessary spacing between functional groups.
• Branching: Reduces activity by disrupting proper alignment and binding efficiency.

4. Terminal Nitrogen Atom

• Tertiary Amine (3° Amine): Maximizes activity by enhancing binding affinity.
• Heterocyclic Incorporation: Incorporating the terminal nitrogen into a heterocyclic ring significantly boosts antihistaminic potency.

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