Improvement of the anxiolytic-like effect of candesartan by its superoxide dismutase mimetic copper(II) complex

CASARSA, B.S.; RODRIGUEZ, I.; WILLIAMS, P.; BAIARDI, G.; BREGONZIO, C.

Córdoba

Congreso; III Reunión Internacional de Ciencias Farmacéuticas; 2014

UNR-UNC-CONICET

There is a large body of evidence, supporting a key role for Ang II in the stress responseacting through its AT1 receptors. It has been already found that candesartan cilexetil(AT1 receptor blocker) administered orally has an anxiolytic effect when tested in theplus maze. Most of the sartans are composed of an appropriately substitutedheterocyclic nucleus coupled to an acidic group (carboxylic or tetrazole) bearingbiphenyl system through a methylene linker. Candesartan has the benzimidazole moietysubstituted with carboxyl functional group at the 7-position. Modifications of thestructure of candesartan by the generation of pharmacodynamic hybrids withantioxidants or NO releasing drugs showed to improve the biological effect of thesartans. Based on this evidence, it was undertaken the design of another class of hybridsby synthesizing coordination compounds with the biometal copper(II) and candesartan.The aim of the present work was to compare the anxiolytic-like effects of candesartancilexetil (Cand) and the new candesartan complex [Cu(Cand)(H2O)4](Cu-Cand). Thiscompound was tested in vivo for the first time. For this purpose, Wistar male rats (250-320 g) were administered orally with Cand or Cu-Cand (3mg/kg), vehicle (NaHCO30.1N) or Cu during 5 days. On day 6 the animals were tested for 5 min in the plus mazeto analyze the time spent in the open arms and extreme arrivals as anxiety index andtotal entries and closed arm entries as locomotor activity index. The data were analyzedusing Anova. The results showed an increase in the anxiolytic parameters in the Cu-Cand respect Cand group. The group Cu was not significant from vehicle. Neither of thecompounds affected the locomotor activity. Cu-Cand showed to be more effective asanxiolytic than Cand. This study provides a new insight into the development ofcopper(II) complexes as potential drugs.