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

2020 ◽  
Vol 21 (10) ◽  
pp. 3411 ◽  
Author(s):  
Dorota Łażewska ◽  
Agnieszka Olejarz-Maciej ◽  
David Reiner ◽  
Maria Kaleta ◽  
Gniewomir Latacz ◽  
...  

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.

2018 ◽  
Vol 28 (23-24) ◽  
pp. 3596-3600 ◽  
Author(s):  
Dorota Łażewska ◽  
Agnieszka Olejarz-Maciej ◽  
Maria Kaleta ◽  
Marek Bajda ◽  
Agata Siwek ◽  
...  

Biomédica ◽  
2019 ◽  
Vol 39 (3) ◽  
pp. 491-501
Author(s):  
María del Pilar Olaya ◽  
Nadezdha Esperanza Vergel ◽  
José Luis López ◽  
María Dolores Viña ◽  
Mario Francisco Guerrero

Introduction: Parkinson’s disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B.Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity.Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively.Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity.Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.


2001 ◽  
Vol 906 (1-2) ◽  
pp. 180-183 ◽  
Author(s):  
Eiichi Sakurai ◽  
Eiko Sakurai ◽  
Yorihisa Tanaka ◽  
Takehiko Watanabe ◽  
Sukhwinder Singh Jossan ◽  
...  

2016 ◽  
Vol 26 (16) ◽  
pp. 4140-4145 ◽  
Author(s):  
Dorota Łażewska ◽  
Jakub Jończyk ◽  
Marek Bajda ◽  
Natalia Szałaj ◽  
Anna Więckowska ◽  
...  

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3580
Author(s):  
Dorota Łażewska ◽  
Paula Zaręba ◽  
Justyna Godyń ◽  
Agata Doroz-Płonka ◽  
Annika Frank ◽  
...  

Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1′-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.


2009 ◽  
Vol 58 (S1) ◽  
pp. 47-48
Author(s):  
K. J. Kuder ◽  
X. Ligneau ◽  
J.-C. Camelin ◽  
D. Łażewska ◽  
J.-C. Schwartz ◽  
...  

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