title: Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT₁A and 5-HT₇ Antagonists in Animal Models.
abstract: The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14-FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15-FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pytka
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Głuch-Lutwin
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mordyl
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Institute of Automatic Control, Silesian University of Technology, Akademicka 16, 44-100, Gliwice, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Olczyk
authors.affiliation: Institute of Automatic Control, Silesian University of Technology, Akademicka 16, 44-100, Gliwice, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Gałuszka
authors.affiliation: Institute of Automatic Control, Silesian University of Technology, Akademicka 16, 44-100, Gliwice, Poland.
authors.forename: Marian
authors.initials: M
authors.lastname: Błachuta
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Waszkielewicz
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D003863:Depression / Q000188:drug therapy*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A