Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-quinuclidinyl benzilate-induced cognitive deficit in rats-Is there a potential for Alzheimer's disease treatment?
Authors: Misik, Jan; Korabecny, Jan; Nepovimova, Eugenie; Kracmarova, Alzbeta; Kassa, Jiri
Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2 mg kg(-1)), administered intraperitoneally 1 h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30 min at the following dose rates; 1 (25.6 mg kg(-1)), 2 (12.3 mg kg(-1)), 3 (5.7 mg kg(-1)), 4 (5.2 mg kg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2 mg kg(-1)) and donepezil (2.65 mg kg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
Structure dependency of a 24-residue peptide humanin on solvent and preferential solvation by trifluoroethanol studied by multicanonical sampling
CHEMICAL PHYSICS LETTERS
Authors: Yagisawa, Ryosuke; Kamiya, Narutoshi; Ikebe, Jinzen; Umezawa, Koji; Higo, Junichi
We performed an enhanced conformation sampling, multicanonical molecular dynamics simulation, of humanin in two solvents: pure water and 30% 2,2,2-trifluoroethanol (TFE)/water co-solvent. Computed helix content at 280 K was 4% in water and 25% in TFE/water. In both solvents, computed free-energy landscape consisted of clearly distinguishable clusters at 280 K. However, the cluster positions in the landscape had no overlap between the water and TFE/water systems. The clusters in TFE/water involved various types of helical structures. Preferential solvation by TFE was seen around the helical regions of humanin. Hydrophobic residues and TFE molecules worked together to induce the helix formation. (c) 2008 Elsevier B. V. All rights reserved.