title: HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties.
abstract: Xanthone derivatives possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study we aimed to investigate antidepressant- and anxiolytic-like properties of a new xanthone derivative - 6-methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-7), as well as its possible mechanism of action, and the influence on cognitive and motor function. HBK-7 in our earlier studies showed high affinity for serotonergic 5-HT1A receptor. We determined the affinity of HBK-7 for CNS receptors and transporters using radioligand assays and examined its intrinsic activity towards 5-HT1A receptor. We evaluated antidepressant- and anxiolytic-like activity of HBK-7 in the mouse forced swim test, and four-plate test, respectively. We examined the influence on locomotor activity in mice to determine if the effect observed in the forced swim test was specific. We used step-through passive avoidance and rotarod tests to evaluate the influence of HBK-7 on cognitive and motor function, respectively. HBK-7 showed moderate affinity for dopaminergic D2 receptor and very low for serotonergic 5-HT2A, adrenergic α2 receptors, as well as serotonin transporter. Functional studies revealed that HBK-7 was a 5-HT1A receptor antagonist. HBK-7 (10mg/kg) decreased immobility time in the forced swim test. Combined treatment with sub-effective doses of HBK-7 and fluoxetine reduced immobility of mice in the forced swim test. Pretreatment with p-chlorophenylalanine and WAY-100,635 antagonized the antidepressant-like effect of HBK-7. Neither of the treatments influenced locomotor activity of mice. HBK-7 at antidepressant-like dose did not impair memory or motor coordination in mice. We demonstrated that HBK-7 was a 5-HT1A receptor antagonist with potent, comparable to mianserin, antidepressant-like activity. HBK-7 mediated its effect through serotonergic system and its antidepressant-like action required the activation of 5-HT1A receptors. At active dose it did not influence cognitive and motor function. Since 5-HT1A receptor antagonists may accelerate the occurrence of antidepressant effect, our findings highlight their potential as future antidepressants.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: karolina.pytka@uj.edu.pl.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pytka
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 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: Barbara
authors.initials: B
authors.lastname: Mordyl
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 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, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka 16, 44-101 Gliwice, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Olczyk
authors.affiliation: Institute of Automatic Control, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka 16, 44-101 Gliwice, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Gałuszka
authors.affiliation: Institute of Automatic Control, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka 16, 44-101 Gliwice, 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 Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D046353:Immobility Response, Tonic; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D045442:Rotarod Performance Test; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; C000617532:HBK-7 compound; D010879:Piperazines; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D044004:Xanthones; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT(1A) receptor antagonist; Antidepressant-like activity; Forced swim test; Mice; Xanthone derivative