Biphenylalkoxyamine Derivatives–Histamine H₃ Receptor Ligands with Butyrylcholinesterase Inhibitory Activity

• Published in: Molecules
• Main Authors: Dorota Łażewska, Paula Zaręba, Justyna Godyń, Agata Doroz-Płonka, Annika Frank, David Reiner-Link, Marek Bajda, Dorota Stary, Szczepan Mogilski, Agnieszka Olejarz-Maciej, Maria Kaleta, Holger Stark, Barbara Malawska, Katarzyna Kieć-Kononowicz
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Subjects: multi-target ligands; histamine H₃ receptor ligands; butyrylcholinesterase inhibitors; monoamine oxidase inhibitors; Alzheimer’s disease
• Online Access: https://www.mdpi.com/1420-3049/26/12/3580

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 (<i>K_i</i> < 150 nM) and submicromolar inhibition of BuChE (IC₅₀ < 1 µM). Among all the tested compounds, <b>19</b> (<b>E153,</b> 1-(5-([1,1′-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H₃R, with a <i>K</i>_i value of 33.9 nM, and for <i>equine</i> <i>serum</i> BuChE, with an IC₅₀ of 590 nM. Moreover, <b>19</b> (<b>E153</b>) 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 <b>19</b> (<b>E153</b>) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound <b>19</b> can be a lead structure for developing new anti-AD agents.