To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with Ki values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist 28 can be considered as a good lead for discovery of novel 5-HT7R antagonists as antidepressants.

01 Jan 2016·Indian Journal of PharmacologyQ4 · MEDICINE

The antidepressant- and anxiolytic-like activities of new xanthone derivative with piperazine moiety in behavioral tests in mice

Q4 · MEDICINE

Article

Author: Olczyk, Adrian ; Waszkielewicz, Anna ; Rapacz, Anna ; Marona, Henryk ; Żmudzka, Elżbieta ; Sapa, Jacek ; Lustyk, Klaudia ; Pytka, Karolina ; Barbara, Filipek ; Gałuszka, Adam

OBJECTIVESXanthones are flavonoids with numerous activities, including antioxidant, antidepressant., or anxiolytic-like. Therefore, the aim of our study was to determine antidepressant- and anxiolytic-like properties of four xanthone derivatives (3-chloro-5-[(4-methylpiperazin-1-yl)methyl]-9H-xanthen-9-one dihydrochloride [HBK-5], 6-methoxy-2-[(4-methylpiperazin-1-yl) methyl]-9H-xanthen-9-one dihydrochloride, 2-[(4-benzylpiperazin-1-yl) methyl]-6-methoxy-9H-xanthen-9-one dihydrochloride, 2-{[4-(2-methoxyphenyl) piperazin-1-yl] methyl}-9H-xanthen-9-one hydrochloride), as well as the influence on cognitive and motor function of active compounds, using animal models.MATERIALS AND METHODSTo determine the antidepressant-like activity, we used forced swim test (FST) and tail suspension test (TST) in mice. We evaluated anxiolytic-like properties in the four-plate test in mice. We studied the influence on cognitive and motor function in passive avoidance step-through and chimney tests, respectively.RESULTSThe antidepressant-like activity (in both FST and TST) showed only HBK-5. Moreover, the compound was also active in the four-plate test, which suggests that it possessed anxiolytic-like properties. HBK-5 did not cause any cognitive and motor deficits in mice at antidepressant- and anxiolytic-like doses.CONCLUSIONSHBK-5 may have potential in the treatment of depression or anxiety disorders, but this issue needs further studies.

01 Oct 2015·European Journal of PharmacologyQ3 · MEDICINE

The antidepressant-like activity of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one involves serotonergic 5-HT1A and 5-HT2A/C receptors activation

Q3 · MEDICINE

Article

Author: Marona, Henryk ; Walczak, Maria ; Kazek, Grzegorz ; Kij, Agnieszka ; Siwek, Agata ; Waszkielewicz, Anna ; Sapa, Jacek ; Gałuszka, Adam ; Pytka, Karolina ; Filipek, Barbara ; Rapacz, Anna ; Olczyk, Adrian

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 5HT1A receptor antagonist - WAY-1006335 and 5HT2A/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 5HT1A and 5HT2A/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. 5HT2A/C receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies.

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Indication	Highest Phase	Country/Location	Organization	Date
Neuroinflammation	Preclinical	ES	Universidad Autónoma de Madrid	09 Feb 2021

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