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HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties.

HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties.

Authors :
Pytka K
Kazek G
Siwek A
Mordyl B
Głuch-Lutwin M
Rapacz A
Olczyk A
Gałuszka A
Waszkielewicz A
Marona H
Sapa J
Filipek B
Zygmunt M
Source :
Pharmacology, biochemistry, and behavior [Pharmacol Biochem Behav] 2016 Jul-Aug; Vol. 146-147, pp. 35-43. Date of Electronic Publication: 2016 Apr 27.
Publication Year :
2016

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.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1873-5177
Volume :
146-147
Database :
MEDLINE
Journal :
Pharmacology, biochemistry, and behavior
Publication Type :
Academic Journal
Accession number :
27132236
Full Text :
https://doi.org/10.1016/j.pbb.2016.04.005