title: Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands.
abstract: In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Łażewska
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Jończyk
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Szałaj
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Więckowska
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Panek
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Moore
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuder
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: mfkonono@cyr-kr.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000588:Amines / Q000737:chemistry*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000621413:1-(7-(4-chlorophenoxy)heptyl)homopiperidine; D000588:Amines; D002800:Cholinesterase Inhibitors; D008024:Ligands; D010880:Piperidines; D018100:Receptors, Histamine H3; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; Chlorophenoxy derivatives; Histamine H3 receptor; Multifunctional ligands