Structure-activity relationships of histamine H2-agonists, a new class of positive inotropic drugs

Agents Actions Suppl. 1991;33:231-56. doi: 10.1007/978-3-0348-7309-3_15.

Abstract

The cimetidine-like moiety in impromidine was replaced by either alternative partial structures known from H2-antagonists or by H2-nonspecific lipophilic groups. The most potent H2-agonists were found in a series of compounds structurally derived from the H1-antagonist pheniramine. Arpromidine (N1-[3-(4-fluorophenyl)-3-(2-pyridinyl)propyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) may be considered a new lead for the development of "cardiohistaminergics". This guanidine combines both about 100 times the potency of histamine in the isolated guinea-pig atrium (pD2 = 8.0) and H1-antagonistic activity (pA2 = 7.65) in the range of pheniramine. Analogues difluorinated in 3,4-(BU-E-75) or 3,5-position (BU-E-76) or chlorinated in 3,4-position (BU-E-64) are up to 160 times more potent H2-agonists than histamine. In contrast to other types of guanidines, in the arpromidine series the order of potency found in guinea-pig atria was in good agreement with the results from isolated perfused guinea-pig hearts. In particular, the two-fold halogenated arpromidine analogues proved to be more potent positive inotropic agents than impromidine with lower stimulating effects on heart rate and reduced arrhythmogenic properties.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Atrial Function
  • Guanidines / chemical synthesis
  • Guanidines / chemistry
  • Guanidines / pharmacology*
  • Guinea Pigs
  • Heart Atria / drug effects
  • Heart Rate / drug effects
  • Hemodynamics / drug effects
  • Ileum / drug effects
  • Ileum / physiology
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Impromidine
  • Molecular Structure
  • Myocardial Contraction / drug effects
  • Papillary Muscles / drug effects
  • Papillary Muscles / physiology
  • Pheniramine / pharmacology
  • Receptors, Histamine H2 / drug effects*
  • Stimulation, Chemical
  • Structure-Activity Relationship

Substances

  • Guanidines
  • Imidazoles
  • Receptors, Histamine H2
  • Pheniramine
  • arpromidine
  • Impromidine