Synthesis and preliminary pharmacological investigation of new N-substituted-N-[ω-(ω-phenoxy-alkylpiperazin-1-yl)alkyl]guanidines as non-imidazole histamine H(3) antagonists

Arch Pharm (Weinheim). 2012 Jun;345(6):431-43. doi: 10.1002/ardp.201100428. Epub 2012 Mar 13.

Abstract

Novel, potent non-imidazole histamine H(3) receptor antagonists were prepared. Detailed structure-activity studies revealed that N-(4-trifluoromethylbenzyl)-N-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine (pA(2) = 8.49 ± 0.05), 1h, and N-(4-nitrobenzyl)-N-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine (pA(2) = 8.43 ± 0.05), 1l, exhibit high affinity for the H(3) histamine receptor. The most potent antagonists in this series, 1e, 1h, and 1l, were also in vitro tested as H(1) receptor antagonists, showing weak H(1) -antagonistic activity with pA(2) = 6.70 ± 0.09, pA(2) = 6.46 ± 0.09, and pA(2) = 6.65 ± 0.11, respectively.

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • Guanidines / chemical synthesis*
  • Guanidines / chemistry
  • Guanidines / pharmacology
  • Guinea Pigs
  • Histamine H3 Antagonists / chemical synthesis*
  • Histamine H3 Antagonists / chemistry
  • Histamine H3 Antagonists / pharmacology
  • In Vitro Techniques
  • Jejunum / drug effects
  • Jejunum / metabolism
  • Male
  • Molecular Structure
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Binding
  • Receptors, Histamine H1 / metabolism
  • Receptors, Histamine H3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Guanidines
  • Histamine H3 Antagonists
  • N-(4-nitrobenzyl)-N-(4-(7-phenoxyheptylpiperazin-1-yl)butyl)guanidine
  • N-(4-trifluoromethylbenzyl)-N-(4-(7-phenoxyheptylpiperazin-1-yl)butyl)guanidine
  • Piperazines
  • Receptors, Histamine H1
  • Receptors, Histamine H3