Dual Target Ligands with 4-tert-Butylphenoxy Scaffold as Histamine H<sub>3</sub> Receptor Antagonists and Monoamine Oxidase B Inhibitors
2020
Dorota Łażewska | Agnieszka Olejarz-Maciej | David Reiner | Maria Kaleta | Gniewomir Latacz | Małgorzata Zygmunt | Agata Doroz-Płonka | Tadeusz Karcz | Annika Frank | Holger Stark | Katarzyna Kieć-Kononowicz
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<sub>3</sub> receptor (H<sub>3</sub>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<sub>3</sub>R (hH<sub>3</sub>R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH<sub>3</sub>R affinities with K<sub>i</sub> values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC<sub>50</sub> values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH<sub>3</sub>R: K<sub>i</sub> = 38 nM and hMAO B: IC<sub>50</sub> = 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.
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