1. Dual Target Ligands with 4-tert-Butylphenoxy Scaffold as Histamine H3 Receptor Antagonists and Monoamine Oxidase B Inhibitors
- Author
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David Reiner, Maria Kaleta, Gniewomir Latacz, Agata Doroz-Płonka, Agnieszka Olejarz-Maciej, Tadeusz Karcz, Holger Stark, Katarzyna Kieć-Kononowicz, Małgorzata Zygmunt, Dorota Łażewska, and Annika Frank
- Subjects
Male ,Ligands ,01 natural sciences ,lcsh:Chemistry ,chemistry.chemical_compound ,0302 clinical medicine ,neurodegenerative disease ,histamine H3 receptor ,inhibitors ,4-tert-butylphenyl derivatives ,Amines ,lcsh:QH301-705.5 ,Spectroscopy ,antagonists ,Molecular Structure ,Parkinson Disease ,General Medicine ,Computer Science Applications ,monoamine oxidase B ,Monoamine oxidase B ,Piperidine ,Histamine H3 receptor ,medicine.drug ,Histamine H3 Antagonists ,Monoamine Oxidase Inhibitors ,Stereochemistry ,Catalepsy ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Structure-Activity Relationship ,In vivo ,Dopamine ,Neuroblastoma ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Rats, Wistar ,Molecular Biology ,IC50 ,Monoamine Oxidase ,creativecommons.org/licenses/by/4.0/pl/legalcode [http] ,Cell Proliferation ,dual-target ligands ,010405 organic chemistry ,Organic Chemistry ,medicine.disease ,0104 chemical sciences ,nervous system diseases ,Kinetics ,HEK293 Cells ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Parkinson’s disease ,Haloperidol ,030217 neurology & neurosurgery - Abstract
Dual target ligands are a promising concept for the treatment of Parkinson&rsquo, 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.
- Published
- 2020
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