The Structure-Activity Relationship (SAR) of H₁ Receptor Antagonist Antihistamines 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 (Structure f H₁ Receptor Antagonist 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.
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.
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.
Alkyl Chain
Ethylene Chain: Essential for activity, providing necessary spacing between functional groups.
Branching: Reduces activity by disrupting proper alignment and binding efficiency.
All antihistamines contain this general chain.
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.
First generation H1-Antagonist