Dual Target Ligands with 4-Butylphenoxy Scaffold as Histamine H Receptor Antagonists and Monoamine Oxidase B Inhibitors.

Dual target ligands are a promising concept for the treatment of Parkinson's disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H receptor (HR) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4--butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4--butylphenoxy)propyl)piperidine (). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human HR (hHR) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hHR affinities with K values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC values below 50 nM. However, the most balanced activity against both biological targets showed (hHR: K = 38 nM and hMAO B: IC = 48 nM). Thus, was chosen for further studies, revealing the nontoxic nature of in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight.