{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:48:16Z","timestamp":1790380096674,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Science Centre, Poland","award":["UMO-2016\/23\/B\/NZ7\/02327"],"award-info":[{"award-number":["UMO-2016\/23\/B\/NZ7\/02327"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neurodegenerative diseases, e.g., Alzheimer\u2019s 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 &lt; 150 nM) and submicromolar inhibition of BuChE (IC50 &lt; 1 \u00b5M). Among all the tested compounds, 19 (E153, 1-(5-([1,1\u2032-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\u00a0serum 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.<\/jats:p>","DOI":"10.3390\/molecules26123580","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T12:44:37Z","timestamp":1623415477000},"page":"3580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Biphenylalkoxyamine Derivatives\u2013Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8454-4440","authenticated-orcid":false,"given":"Dorota","family":"\u0141a\u017cewska","sequence":"first","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Zar\u0119ba","sequence":"additional","affiliation":[{"name":"Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0295-2772","authenticated-orcid":false,"given":"Justyna","family":"Gody\u0144","sequence":"additional","affiliation":[{"name":"Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Doroz-P\u0142onka","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Frank","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstr. 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1514-2215","authenticated-orcid":false,"given":"David","family":"Reiner-Link","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstr. 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6032-0354","authenticated-orcid":false,"given":"Marek","family":"Bajda","sequence":"additional","affiliation":[{"name":"Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8503-9961","authenticated-orcid":false,"given":"Dorota","family":"Stary","sequence":"additional","affiliation":[{"name":"Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3072-8890","authenticated-orcid":false,"given":"Szczepan","family":"Mogilski","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamic, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1466-0742","authenticated-orcid":false,"given":"Agnieszka","family":"Olejarz-Maciej","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kaleta","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3336-1710","authenticated-orcid":false,"given":"Holger","family":"Stark","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstr. 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Malawska","sequence":"additional","affiliation":[{"name":"Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-7443","authenticated-orcid":false,"given":"Katarzyna","family":"Kie\u0107-Kononowicz","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.ejmech.2017.03.062","article-title":"Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer\u2019s disease","volume":"132","author":"Li","year":"2017","journal-title":"Eur. 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