Abstract
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.
Highlights
Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes catalyzing the hydrolysis of acetylcholine (ACh)
All compounds were screened for human monoamine oxidase B inhibitory activity, as research showed that the MAO B level is increased in Alzheimer’s disease (AD) neurons and overexpression of this enzyme enhances β-amyloid production via γ-secrewards AChE from the electric eel and BuChE from equine serum
All compounds were screened for human monoamine oxidase B inhibitory activity, as research showed that the MAO B level is increased in AD neurons and overexpression of this enzyme enhances β-amyloid production via γ-secretase [20]
Summary
Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes catalyzing the hydrolysis of acetylcholine (ACh). BuChE is mainly expressed in regions that are important for cognition and behavior (e.g., in white matter and glia) [1]. The physiological function of BuChE is still unclear but increased activity of this enzyme has been observed. Molecules 2021f,u26n,c3t5i8o0n of BuChE is still unclear but increased activity of this enzyme has been observed in 2 of 18 some diseases, e.g., neurodegenerative ones including Alzheimer’s disease (AD) and Parkinson’s disease (PD), uremia, obesity, hyperthyroidism and diabetes [1]. Belong to the family of GPCR receptors. They are mostly present in the brain in the region connected with memory and wakefulness [9]. TbheeacpthivaartmedascpoolongtaynoeofuHsl3yRwisitchoomutptlhiceaptereds,ence of an as many splices haagvoenibstee[9n].dInesitciarillbye, dH3wRitlihgadnidffsewreenrte fduensccrtiiboends,asansidngfluerttahregremt coormeproeucenpdsto, brsut recently, show constitutiveasacthtievgiteynearnadl tceanndebnecyacintivmaetdedicisnpaol cnhtaemneisoturyslhyaws cihthaonugetdth[1e3p],rmesuelntic-teaorgfeatinng ligands agonist [9].
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