Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands

Katarzyna Szczepańska, Tadeusz Karcz, Szczepan Mogilski, Agata Siwek, Kamil J. Kuder, Gniewomir Latacz, Monika Kubacka, Stefanie Hagenow, Annamaria Lubelska, Agnieszka Olejarz, Magdalena Kotańska, Bassem Sadek, Holger Stark, Katarzyna Kieć-Kononowicz

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2−25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0–120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands.

Original languageEnglish
Pages (from-to)223-234
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - May 25 2018


  • Anticonvulsants
  • Histamine H receptor
  • Histamine H receptor ligands
  • Metabolic stability
  • Molecular docking
  • Non-imidazole histamine HR ligands
  • Piperazine derivatives
  • Pro-cognitives

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


Dive into the research topics of 'Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands'. Together they form a unique fingerprint.

Cite this