The antidepressant-like activity of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one involves serotonergic 5-HT_1A and 5-HT_2A/C receptors activation

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• 作者：Karolina Pytka^a ; ^{karolina.pytka@uj.edu.pl" class="auth_mail" title="E-mail the corresponding author} ; Maria Walczak^b ; ^c ; Agnieszka Kij^c ; Anna Rapacz^a ; Agata Siwek^d ; Grzegorz Kazek^a ; Adrian Olczyk^e ; Adam Ga艂uszka^e ; Anna Waszkielewicz^f ; Henryk Marona^f ; Jacek Sapa^a ; Barbara Filipek^a
• 关键词：Antidepressant-like activity ; 5-HT1A receptor ; 5-HT2 receptor ; Bioavailability ; Distribution in brain ; Mass spectrometry
• 刊名：European Journal of Pharmacology
• 出版年：2015
• 出版时间：5 October 2015
• 年：2015
• 卷：764
• 期：Complete
• 页码：537-546
• 全文大小：550 K

文摘

Xanthone derivatives have been shown to posses many biological properties. Some of them act within the central nervous system and show neuroprotective or antidepressant-like properties. Taking this into account we investigated antidepressant-like activity in mice and the possible mechanism of action of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-11) – a new xanthone derivative. We demonstrated that HBK-11 produced antidepressant-like effects in the forced swim test and tail suspension test, comparable to that of venlafaxine. The combined treatment with sub-effective doses of HBK-11 and fluoxetine (but not reboxetine or bupropion) significantly reduced the immobility in the forced swim test. Moreover, the antidepressant-like activity of HBK-11 in the aforementioned test was blocked by p-chlorophenylalanine, and significantly reduced by serotonergic 5HT_1A receptor antagonist – WAY-1006335 and 5HT_2A/C receptor antagonist – ritanserin. As none of the above treatments influenced the spontaneous locomotor activity, it can be concluded that HBK-11 mediates its activity through a serotonergic system, and its antidepressant-like effect involves 5HT_1A and 5HT_2A/C receptor activation. Furthermore, at antidepressant-like doses HBK-11 did not cause the mice to display locomotor deficits in rotarod or chimney tests. Considering the pharmacokinetic profile, HBK-11 demonstrated rapid absorption after i.p. administration, high clearance value, short terminal half-life, very high volume of distribution and incomplete bioavailability. The compound studied had good penetration into the brain tissue of mice. Since studied xanthone derivative seems to present interesting, untypical mechanism of antidepressant-like action i.e. 5HT_2A/C receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies.