Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT6R ligands with noticeable action on AChE/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease

被引：8

作者：

Czarnota-Lydka, Kinga ^{[1
,2
]}

Sudol-Talaj, Sylwia ^{[1
,2
]}

Kucwaj-Brysz, Katarzyna ^{[1
]}

Kurczab, Rafal ^{[3
]}

Satala, Grzegorz ^{[3
]}

de Candia, Modesto ^{[4
]}

Samarelli, Francesco ^{[4
]}

Altomare, Cosimo Damiano ^{[4
]}

Carocci, Alessia ^{[4
]}

Barbarossa, Alexia ^{[4
]}

Zeslawska, Ewa ^{[5
]}

Gluch-Lutwin, Monika ^{[6
]}

Mordyl, Barbara ^{[6
]}

Kubacka, Monika ^{[7
]}

Wilczynska-Zawal, Natalia ^{[8
]}

Jastrzebska-Wiesek, Magdalena ^{[8
]}

Partyka, Anna ^{[8
]}

Khan, Nadia ^{[1
,2
,10
]}

Wiecek, Malgorzata ^{[1
]}

Nitek, Wojciech ^{[9
]}

Honkisz-Orzechowska, Ewelina ^{[1
]}

Latacz, Gniewomir ^{[1
]}

Wesolowska, Anna ^{[8
]}

Carrieri, Antonio ^{[4
]}

Handzlik, Jadwiga ^{[1
]}

机构：

[1] Jagiellonian Univ, Med Coll, Dept Technol & Biotechnol Drugs, Med 9, PL-30688 Krakow, Poland

[2] Jagiellonian Univ Med Coll, Doctoral Sch Med & Hlth Sci, Sw Lazarza 15, PL-31530 Krakow, Poland

[3] Polish Acad Sci, Dept Med Chem, Maj Inst Pharmacol, Smetna 12, PL- 313343 Krakow, Poland

[4] Univ Bari Aldo Moro, Dept Pharm Drug Sci, Via E Orabona 4, I-70125 Bari, Italy

[5] Pedag Univ Krakow, Inst Biol & Earth Sci, Podchorazych 2, PL-30084 Krakow, Poland

[6] Jagiellonian Univ, Dept Pharmacobiol, Med Coll, Med 9, PL-30688 Krakow, Poland

[7] Jagiellonian Univ, Med Coll, Dept Pharmacodynam, Med 9, PL-30688 Krakow, Poland

[8] Jagiellonian Univ, Med Coll, Dept Clin Pharm, Med 9, PL-30688 Krakow, Poland

[9] Jagiellonian Univ, Fac Chem, Gronostajowa 2, PL-30087 Krakow, Poland

[10] Jagiellonian Univ, Med Coll, Dept Pathophysiol, Czysta 18, PL-31121 Krakow, Poland

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 259卷

关键词：

5-HT6 serotonin receptors; 1,3,5-Triazine; Thioether; ADME-Tox; Behavioral tests; CACO-2 CELL MONOLAYER; OBJECT RECOGNITION; RECEPTOR ANTAGONIST; CRYSTAL-STRUCTURE; OXIDATIVE STRESS; FORCE-FIELD; BASIS-SETS; IN-VITRO; MEMORY; DERIVATIVES;

D O I：

10.1016/j.ejmech.2023.115695

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT6 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 5HT6 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-i < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, 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-HT6 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-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.

引用

页数：22