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

• Published in: International journal of molecular sciences 2020-05, Vol.21 (10), p.3411
• Main Authors: Łażewska, Dorota, Olejarz-Maciej, Agnieszka, Reiner, David, Kaleta, Maria, Latacz, Gniewomir, Zygmunt, Małgorzata, Doroz-Płonka, Agata, Karcz, Tadeusz, Frank, Annika, Stark, Holger, Kieć-Kononowicz, Katarzyna
• Format: Article
• Language: English
• Subjects: 4-tert-butylphenyl derivatives; Affinity; Amine oxidase (flavin-containing); Amines; antagonists; Biological activity; Body weight; Brain; Catalepsy; Disease; Dopamine; dual-target ligands; Elongation; Enzymes; Haloperidol; Histamine; histamine H3 receptor; Histamine H3 receptors; Hydrogen peroxide; In vivo methods and tests; Influence; inhibitors; Ligands; monoamine oxidase B; Neuroblastoma; Neuroprotection; Oxidative stress; Parkinson's disease; Pharmaceutical industry; Piperidine; Potassium; Sleep disorders
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21103411

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 H3 receptor (H3R) 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 H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 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.