Pytka Karolina, Walczak Maria, Kij Agnieszka, Rapacz Anna, Siwek Agata, Kazek Grzegorz, Olczyk Adrian, Gałuszka Adam, Waszkielewicz Anna, Marona Henryk, Sapa Jacek, Filipek Barbara
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
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.
Eur J Pharmacol. 2015 Oct 5;764:537-546. doi: 10.1016/j.ejphar.2015.07.041. Epub 2015 Jul 22.
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.
呫吨酮衍生物已被证明具有多种生物学特性。其中一些在中枢神经系统内发挥作用，并表现出神经保护或类抗抑郁特性。考虑到这一点，我们研究了6-甲氧基-2-[4-(2-甲氧基苯基)哌嗪-1-基]-9H-呫吨-9-酮（HBK-11）——一种新的呫吨酮衍生物在小鼠中的类抗抑郁活性及其可能的作用机制。我们证明，HBK-11在强迫游泳试验和悬尾试验中产生了类抗抑郁作用，与文拉法辛相当。用亚有效剂量的HBK-11和氟西汀（但不是瑞波西汀或安非他酮）联合治疗在强迫游泳试验中显著降低了不动时间。此外，在上述试验中，HBK-11的类抗抑郁活性被对氯苯丙氨酸阻断，并被5-羟色胺能5HT1A受体拮抗剂——WAY-1006335和5HT2A/C受体拮抗剂——利坦色林显著降低。由于上述任何一种处理均未影响自发运动活性，因此可以得出结论，HBK-11通过5-羟色胺能系统介导其活性，其类抗抑郁作用涉及5HT1A和5HT2A/C受体激活。此外，在类抗抑郁剂量下HBK-11在转棒试验或烟囱试验中未导致小鼠出现运动功能缺陷
考虑到药代动力学特征，HBK-11腹腔注射给药后吸收迅速，清除率高，末端半衰期短，分布容积非常大且生物利用度不完全。所研究的化合物对小鼠脑组织具有良好的渗透性。由于所研究的呫吨酮衍生物似乎呈现出有趣的、非典型的类抗抑郁作用机制，即5HT2A/C受体激活，它可能在治疗抑郁症方面具有潜力，当然需要进一步研究。
