title: Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6receptor antagonists. Design, synthesis and biological evaluation.
abstract: As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT6receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT6receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT6receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT6receptor (Kb= 27 nM), acetylcholinesterase and butyrylcholinesterase (IC50hAChE= 12 nM, IC50hBuChE= 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.
authors: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland. Electronic address: anna.wieckowska@uj.edu.pl.
authors: Anna
authors: A
authors: Więckowska
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Marcin
authors: M
authors: Kołaczkowski
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Adam
authors: A
authors: Bucki
authors: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Justyna
authors: J
authors: Godyń
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Monika
authors: M
authors: Marcinkowska
authors: Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Krzysztof
authors: K
authors: Więckowski
authors: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Paula
authors: P
authors: Zaręba
authors: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Agata
authors: A
authors: Siwek
authors: Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Grzegorz
authors: G
authors: Kazek
authors: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Monika
authors: M
authors: Głuch-Lutwin
authors: Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957, Warsaw, Poland.
authors: Paweł
authors: P
authors: Mierzejewski
authors: Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957, Warsaw, Poland.
authors: Przemysław
authors: P
authors: Bienkowski
authors: Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957, Warsaw, Poland.
authors: Halina
authors: H
authors: Sienkiewicz-Jarosz
authors: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia.
authors: Damijan
authors: D
authors: Knez
authors: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Tomasz
authors: T
authors: Wichur
authors: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia.
authors: Stanislav
authors: S
authors: Gobec
authors: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
authors: Barbara
authors: B
authors: Malawska
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000178:diet therapy* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002800:Cholinesterase Inhibitors; D008024:Ligands; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: 5-HT(6) receptor antagonists; Acetylcholinesterase inhibitors; Alzheimer's disease; Butyrylcholinesterase inhibitors; Multi-target-directed ligands