There is a large body of evidence, supporting a key role for Ang II in the stress response acting through its AT1 receptors. It has been already found that candesartan cilexetil (AT1 receptor blocker) administered orally has an anxiolytic effect when tested in the plus maze. Most of the sartans are composed of an appropriately substituted heterocyclic nucleus coupled to an acidic group (carboxylic or tetrazole) bearing biphenyl system through a methylene linker. Candesartan has the benzimidazole moiety substituted with carboxyl functional group at the 7-position. Modifications of the structure of candesartan by the generation of pharmacodynamic hybrids with antioxidants or NO releasing drugs showed to improve the biological effect of the sartans. Based on this evidence, it was undertaken the design of another class of hybrids by synthesizing coordination compounds with the biometal copper(II) and candesartan. The aim of the present work was to compare the anxiolytic-like effects of candesartan cilexetil (Cand) and the new candesartan complex [Cu(Cand)(H2O)4](Cu-Cand). This compound 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 (NaHCO3 0.1N) or Cu during 5 days. On day 6 the animals were tested for 5 min in the plus maze to analyze the time spent in the open arms and extreme arrivals as anxiety index and total entries and closed arm entries as locomotor activity index. The data were analyzed using 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 the compounds affected the locomotor activity. Cu-Cand showed to be more effective as anxiolytic than Cand. This study provides a new insight into the development of copper(II) complexes as potential drugs.
