Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 15, 31-530, Krakow, Poland.
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Krakow, Poland.
Eur J Med Chem. 2023 Nov 5;259:115695. doi: 10.1016/j.ejmech.2023.115695. Epub 2023 Jul 30.
Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (K < 200 nM) and selectivity towards 5-HTR, with respect to 5-HTR, 5-HTR, and DR, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.
阿尔茨海默病正在成为一个日益严重的问题，其发病率呈指数级增长。从治疗角度来看，5-羟色胺 5-HT 受体似乎是一个特别有吸引力的靶点，因为它们不仅参与认知过程，还与抑郁和精神病有关。在这项工作中，我们展示了一系列具有独特 1,3,5-三嗪骨架的 18 种新化合物的合成和广泛的生物学特征，这些化合物是有效的 5-HT 受体配体。这项研究的主要目的是比较新合成的硫衍生物与它们的氧类似物以及首次获得的 N-去甲基化的 O-和 S-代谢物的生物学活性。大多数新的三嗪类化合物在放射性配体结合测定中对 5-HTR 具有高亲和力（K < 200 nM）和选择性，相对于 5-HTR、5-HTR 和 DR。对于选定的活性化合物，进行了晶体学研究、功能生物测定以及体外 ADME-Tox 分析。令人兴奋的新颖之处在于，与迄今为止在该化学类中获得的所有其他化合物以及之前报道的化合物相比，硫衍生物表现出激动剂作用模式。先进的计算研究表明，这种有趣的功能转变可能是由仅由硫原子形成的硫属键引起的。此外，N-去甲基化衍生物表现出很强的抗氧化能力，而且与母体结构相比，其代谢稳定性有显著提高。乙酰胆碱酯酶研究显示 5-HT 激动剂 19 和强效拮抗剂 5 对 AChE 和 BChE 具有微摩尔抑制活性。最后，化合物 19 的行为实验表明其具有抗抑郁样特性和轻微改善认知缺陷的能力，而不会自行引起记忆损伤。两种化合物（5 和 19）的描述性药理学特性为在 1,3,5-三嗪衍生物组中开发具有 5-HT（激动剂和拮抗剂）/AChE 和/或 BChE 机制的多靶化合物提供了设计线索。
