Synthesis and dual histamine H₁ and H₂ receptor antagonist activity of cyanoguanidine derivatives

Molecules. 2013 Nov 15;18(11):14186-202. doi: 10.3390/molecules181114186.

Abstract

Premedication with a combination of histamine H₁ receptor (H₁R) and H₂ receptor (H₂R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H₁R and H₂R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H₁R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H₂R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H₂R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H₁R) and the isolated spontaneously beating right atrium (H₂R) of the guinea pig. The results indicate that, depending on the nature of the H₂R antagonist partial structure, the highest H₁R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H₁R, ileum) and 7.73 (H₂R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H₁R) and 6.61 (H₂R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H₁R and H₂R pharmacophoric moieties with mutually affinity-enhancing properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cimetidine / analogs & derivatives
  • Cimetidine / chemistry
  • Guanidines / chemical synthesis*
  • Guanidines / chemistry*
  • Guinea Pigs
  • Histamine H1 Antagonists / chemical synthesis
  • Histamine H1 Antagonists / chemistry*
  • Histamine H2 Antagonists / chemical synthesis
  • Histamine H2 Antagonists / chemistry*
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Structure
  • Piperidines / chemistry
  • Pyrilamine / chemistry

Substances

  • Guanidines
  • Histamine H1 Antagonists
  • Histamine H2 Antagonists
  • Piperidines
  • Cimetidine
  • tiotidine
  • Pyrilamine
  • dicyandiamido
  • roxatidine acetate