Piperidine variations in search for non-imidazole histamine H3 receptor ligands

Synthesis and biological evaluation of the novel histamine H3 receptor ligands is described. Two series of ethers (aliphatic and aromatic) have been prepared by four different methods. Compounds were evaluated for their affinities at recombinant human H3 receptor stably expressed in CHO cells. The ethers show from low to moderate in vitro affinities in nanomolar concentration range. The most potent compound was the 1-[3-(4-tert-butylphenoxy)propyl]-4-piperidino-piperidine 16 (hH3R Ki = 100 nM). Several members of the new series investigated under in vivo conditions, proved to be inactive.

New aliphatic (4–8) and aromatic (9–16) ethers were prepared and evaluated for binding affinity at the histamine H3 receptor. The bipiperidine derivative 16 has been found as the most potent compound in vitro (hH3Ki = 100 nM). Selected compounds tested in vivo did not show potencies up to > 10 mg/kg po in mice.Figure optionsDownload as PowerPoint slide