title: Novel arylsulfonamide derivatives with 5-HT₆/5-HT₇ receptor antagonism targeting behavioral and psychological symptoms of dementia.
abstract: In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.
authors.affiliation: Adamed Ltd., Pieńków 149, 05-152 Czosnów, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.forename: Monika
authors.initials: M
authors.lastname: Marcinkowska
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mitka
authors.forename: Jolanta
authors.initials: J
authors.lastname: Jaśkowska
authors.forename: Piotr
authors.initials: P
authors.lastname: Kowalski
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.forename: Anna
authors.initials: A
authors.lastname: Wasik
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.forename: Paweł
authors.initials: P
authors.lastname: Mierzejewski
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bienkowski
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced; D003412:Cricetulus; D003704:Dementia / Q000188:drug therapy* / Q000523:psychology; D065127:Dopamine D2 Receptor Antagonists; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001583:Benzoxazoles; D065127:Dopamine D2 Receptor Antagonists; C000590781:N-(4-(4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl)butyl)benzothiophene-2-sulfonamide; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor; C104425:serotonin 7 receptor