Substituent Effect on the Stereochemistry of H2-receptor Antagonists of the Phenylformamidine Series. A Conformation-Dependent Mode of Interaction With the H2 Receptor

J Med Chem. 1991 Jun;34(6):1772-6. doi: 10.1021/jm00110a004.

Abstract

The influence of alkyl substitution on the stereoisomerism of the formamidine cation (E,E vs E,Z) of several N-substituted (imidazolylphenyl)formamidines (1-10) was investigated. As (imidazolylphenyl)formamidines having alkyl substituents of more than three carbon atoms bind to H2-receptor preparations in a pseudoirreversible mode causing unsurmountable antagonism, the four isomeric butylformamidines (5-7 and 9) having comparable lipophilic character but different E,E/E,Z composition were investigated in H2-receptor assays to determine quantitatively any difference in their pseudoirreversible inhibitory pattern. It was found that the geometry of the formamidine cation is affected by the steric bulk of the substituent on the formamidine nitrogen. A relationship between the percentage of the E,E conformation of the formamidine cation and degree of pseudoirreversible antagonism was also found. The present studies support the hypothesis that bidentate hydrogen bonding plays an important role in the interaction of (imidazolylphenyl)formamidines with the H2 receptor.

MeSH terms

  • Amidines / metabolism
  • Amidines / pharmacology*
  • Animals
  • Guinea Pigs
  • Histamine H2 Antagonists* / metabolism
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Conformation
  • Stereoisomerism

Substances

  • Amidines
  • Histamine H2 Antagonists