title: Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.
abstract: We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.
authors.affiliation: Adamed Ltd., Pieńków 149, 05-152 Czosnów, Poland; Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland. Electronic address: marcin.kolaczkowski@adamed.com.pl.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Marcinkowska
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Śniecikowska
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wasik
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Cracow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.affiliation: Institute of Psychiatry and Neurology, 9 Sobieskiego Street, 02-957 Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Mierzejewski
authors.affiliation: Institute of Psychiatry and Neurology, 9 Sobieskiego Street, 02-957 Warsaw, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bienkowski
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003704:Dementia / Q000188:drug therapy* / Q000523:psychology*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013550:Swimming
chemical_list: C000602735:2-propoxybenzeneamide; C000602749:4-(piperazin-1-yl)-1H-indole; C000602750:7-butoxy-3,4-dihydroquinoloin-2(1H)-one; D001549:Benzamides; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor
keywords: 5-HT(6)R antagonist; BPSD; D(2)R partial agonist; Dementia; Designed multiple ligand (DML)