Łażewska Dorota, Siwek Agata, Olejarz-Maciej Agnieszka, Doroz-Płonka Agata, Wiktorowska-Owczarek Anna, Jóźwiak-Bębenista Marta, Reiner-Link David, Frank Annika, Sromek-Trzaskowska Wioletta, Honkisz-Orzechowska Ewelina, Królicka Ewelina, Stark Holger, Wieczorek Marek, Wagner Waldemar, Kieć-Kononowicz Katarzyna, Stasiak Anna
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str., 30-688 Kraków, Poland.
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9 Str, 30-688 Kraków, Poland.
Pharmaceutics. 2022 Oct 13;14(10):2187. doi: 10.3390/pharmaceutics14102187.
The clinical symptoms of Parkinson’s disease (PD) appear when dopamine (DA) concentrations in the striatum drops to around 20%. Simultaneous inhibitory effects on histamine H3 receptor (H3R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H3R (hH3R) affinity and inhibitory activity to human MAO B (hMAO B). Results showed different activity of the compounds towards the two biological targets. Most compounds had poor affinity for hH3R (Ki > 500 nM), but very good inhibitory potency for hMAO B (IC50 < 50 nM). After further in vitro testing (modality of MAO B inhibition, permeability in PAMPA assay, cytotoxicity on human astrocyte cell lines), the most promising dual-acting ligand, 1-(3-(4-(tert-butyl)phenoxy)propyl)-2-methylpyrrolidine (13: hH3R: Ki = 25 nM; hMAO B IC50 = 4 nM) was selected for in vivo evaluation. Studies in rats of compound 13, in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects for H3R (decline in food and a water consumption), decline in MAO B activity (>90%) in rat cerebral cortex (CTX), and an increase in DA content in CTX and striatum. Moreover, compound 13 caused a slight increase in noradrenaline, but a reduction in serotonin concentration in CTX. Thus, compound 13 is a promising dual-active ligand for the potential treatment of PD although further studies are needed to confirm this.
当纹状体中多巴胺（DA）浓度降至约20%时，帕金森病（PD）的临床症状就会出现。对组胺H3受体（H3R）和单胺氧化酶B（MAO B）的同时抑制作用可提高大脑中的DA水平。设计了一系列化合物，并在体外测试了它们对人H3受体（hH3R）的亲和力以及对人MAO B（hMAO B）的抑制活性。结果显示这些化合物对这两个生物学靶点具有不同的活性。大多数化合物对hH3R的亲和力较差（Ki>500 nM），但对hMAO B具有非常好的抑制效力（IC50<50 nM）。经过进一步的体外测试（MAO B抑制方式、PAMPA试验中的通透性、对人星形胶质细胞系的细胞毒性），选择了最有前景的双效配体1-(3-(4-(叔丁基)苯氧基)丙基)-2-甲基吡咯烷（13：hH3R：Ki = 25 nM；hMAO B IC50 = 4 nM）进行体内评估。对体重为3 mg/kg的化合物13进行的大鼠研究证实了其对H3R的拮抗作用（食物和水消耗量下降）、大鼠大脑皮层（CTX）中MAO B活性下降（>90%）以及CTX和纹状体中DA含量增加。此外，化合物13使去甲肾上腺素略有增加，但使CTX中的血清素浓度降低。因此，尽管需要进一步研究来证实，但化合物13是一种有前景的双活性配体，有可能用于治疗PD。
