Cios Agnieszka, Chłoń-Rzepa Grażyna, Jastrzębska-Więsek Magdalena, Pociecha Krzysztof, Wójcik-Pszczoła Katarzyna, Pękala Elżbieta, Wesołowska Anna
Department of Clinical Pharmacy, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, Kraków, 30-688, Poland.
Department of Medicinal Chemistry, Faculty of Pharmacy, Medyczna 9, Kraków, 30-688, Poland.
Pharmacol Rep. 2025 Feb;77(1):158-171. doi: 10.1007/s43440-024-00686-2. Epub 2024 Dec 16.
Research on new candidates for antidepressant/anxiolytic drugs from the long-chain arylpiperazines (LCAPs) group containing a 1,3-dimethylpurine-2,6-dione as a terminal amide fragment fits into the modern exploration trend. This study aimed to examine, for the first time in male Wistar rats, pharmacodynamic (antidepressant- and anxiolytic-like) and pharmacokinetic properties of 7-(5-(4-(3-chlorophenyl)piperazin-1-yl)pentyl)-1,3-dimethyl-3,7-dihydro-1 H-purine-2,6-dione hydrochloride (GR-14).
Antidepressant- and anxiolytic-like activities have been assessed in the forced swim test (FST) and Vogel conflict drinking test, respectively. The pharmacokinetic characteristics of GR-14, its distribution into rat tissues, and several in vitro ADME-Tox parameters (hepatocytotoxic, neurocytotoxic, metabolic stability) have been defined.
GR-14 produces strong and dose-dependent antidepressant- and anxiolytic-like effects in both tests used. Pharmacokinetic findings demonstrate that GR-14 reveals linear pharmacokinetics tested after intravenous (iv) and was rapidly absorbed after oral (po) administration. It rapidly crosses the blood-brain barrier (BBB) which is vital for therapeutic effects in vivo in psychiatric diseases, depression, and anxiety. Moreover, it is slowly eliminated from the brain, maintaining concentrations higher than those in plasma at the last time point measured. Further studies have also shown that GR-14 is an average high-clearance drug in rat liver microsomes and exerts neither hepatocytotoxic nor neurocytotoxic effects in vitro.
The tested derivative GR-14 presents prominent mood-modulating activity in rats and has promising pharmacokinetic parameters and a good safety profile. The beneficial pharmacology and pharmacokinetics of GR-14 in vivo are in high concordance with its profile in vitro, thus underlining very hopeful properties to support the early development process.
从含有1,3 - 二甲基嘌呤 - 2,6 - 二酮作为末端酰胺片段的长链芳基哌嗪（LCAPs）组中寻找新型抗抑郁/抗焦虑药物的研究符合现代探索趋势。本研究旨在首次在雄性Wistar大鼠中检测7 - (5 - (4 - (3 - 氯苯基)哌嗪 - 1 - 基)戊基)-1,3 - 二甲基 - 3,7 - 二氢 - 1H - 嘌呤 - 2,6 - 二酮盐酸盐（GR - 14）的药效学（抗抑郁和抗焦虑样）及药代动力学特性。
分别在强迫游泳试验（FST）和Vogel冲突饮水试验中评估抗抑郁和抗焦虑样活性。确定了GR - 14的药代动力学特征、其在大鼠组织中的分布以及几个体外ADME - Tox参数（肝细胞毒性、神经细胞毒性、代谢稳定性）。
在所用的两种试验中，GR - 14均产生强烈且剂量依赖性的抗抑郁和抗焦虑样作用。药代动力学研究结果表明，GR - 14静脉注射（iv）后呈现线性药代动力学，口服（po）给药后迅速吸收。它能迅速穿过血脑屏障（BBB），这对精神疾病、抑郁症和焦虑症的体内治疗效果至关重要。此外，它从大脑中缓慢消除，在最后测量时间点时大脑中的浓度维持高于血浆中的浓度。进一步研究还表明，GR - 14在大鼠肝微粒体中是一种平均高清除率药物，并且在体外既不产生肝细胞毒性也不产生神经细胞毒性作用。
受试衍生物GR - 14在大鼠中呈现出显著的情绪调节活性，具有良好的药代动力学参数和安全性。GR - 14在体内的有益药理学和药代动力学与其体外特征高度一致，从而突出了其非常有希望支持早期开发过程的特性。
