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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 3 receptor (H 3 R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4- tert -butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4- tert -butylphenoxy)propyl)piperidine ( DL76 ). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H 3 R (hH 3 R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH 3 R affinities with K i values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC 50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH 3 R: K i = 38 nM and hMAO B: IC 50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight.

Dual Target Ligands with 4-tert-Butylphenoxy Scaffold as Histamine H3 Receptor Antagonists and Monoamine Oxidase B Inhibitors