title: 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.
abstract: 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.
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 Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland; Jagiellonian Centre for Experimental Therapeutics, Bobrzyńskiego 14, 30-348 Krakow, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Walczak
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics, Bobrzyńskiego 14, 30-348 Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kij
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: Department of Pharmacobiology, Chair of Organic Chemistry, 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 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: Institute of Automatic Control, 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, Silesian University of Technology, Akademicka 16, 44-101 Gliwice, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Gałuszka
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
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects* / Q000378:metabolism; D045442:Rotarod Performance Test; D058825:Serotonin 5-HT1 Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D013550:Swimming; D014966:Xanthenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D044004:Xanthones / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C000609175:6-methoxy-2-(4-(2-methoxyphenyl)piperazin-1-yl)-9H-xanthen-9-one; D000928:Antidepressive Agents; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D014966:Xanthenes; D044004:Xanthones; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT(1A) receptor; 5-HT(2) receptor; Antidepressant-like activity; Bioavailability; Distribution in brain; Mass spectrometry