Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1Areceptor partial agonists

被引：8

作者：

Partyka, Anna ^{[1
]}

Zagorska, Agnieszka ^{[2
]}

Kotanska, Magdalena ^{[3
]}

Walczak, Maria ^{[4
]}

Jastrzebska-Wiesek, Magdalena ^{[1
]}

Knutelska, Joanna ^{[3
]}

Bednarski, Marek ^{[3
]}

Gluch-Lutwin, Monika ^{[5
]}

Mordyl, Barbara ^{[5
]}

Janiszewska, Paulina ^{[4
]}

Wesolowska, Anna ^{[1
]}

机构：

[1] Jagiellonian Univ, Fac Pharm, Dept Clin Pharm, Coll Med, Krakow, Poland

[2] Jagiellonian Univ, Fac Pharm, Dept Med Chem, Coll Med, Krakow, Poland

[3] Jagiellonian Univ, Fac Pharm, Dept Pharmacol Screening, Coll Med, Krakow, Poland

[4] Jagiellonian Univ, Fac Pharm, Chair & Dept Toxicol, Coll Med, Krakow, Poland

[5] Jagiellonian Univ, Fac Pharm, Dept Pharmacobiol, Coll Med, Krakow, Poland

来源：

PLOS ONE | 2020年 / 15卷 / 08期

关键词：

RECEPTOR ANTAGONIST; DEPRESSIVE DISORDER; PREFRONTAL CORTEX; ERK ACTIVATION; BODY-WEIGHT; MAP KINASE; 5-HT7; AUGMENTATION; PHARMACOLOGY; LIGANDS;

D O I：

10.1371/journal.pone.0237196

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT(1A)receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT(1A)receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models throughin vitroandin vivoexperiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT(1A)receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger alpha(1)-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action.

引用

页数：30

共 61 条

[31] Disrupted MEK/ERK signaling in the medial orbital cortex and dorsal endopiriform nuclei of the prefrontal cortex in a chronic restraint stress mouse model of depression [J].