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New dual binding site acetylcholinesterase ( ACh E) inhibitors have been designed and synthesized as a new drug candidate for the treatment of Alzheimer's disease ( AD) through the binding to both catalytic and peripheral sites of the enzyme. Therefore, a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives 6a- j were synthesized and investigated for their ability to inhibit the activity of human ACh E ( hAChE) in comparison with huperzine-A. All the compounds were found to inhibit ACh E activity, especially compounds 6c and 6i with the inhibition value of 76.10% and 77.82%, respectively. The molecular docking study indicated that they were nicely accommodated by ACh E. The molecular docking study revealed that 6c and 6i possessed a more optimal binding conformation than 6a and can perfectly fit into the active and peripheral site of hAChE, and consequently exhibited highly improved inhibitor potency to hAChE. [ABSTRACT FROM AUTHOR]

Abstract: A series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives 7a–i were synthesized and evaluated as novel acetylcholinesterase (AChE) inhibitors. All target compounds were evaluated in vitro for the inhibitory activities against AChE via Ellman colorimetric assay. Compound 7c showed an excellent (89.82%) inhibitory activity. The molecular docking studies revealed that 7c, 7d and 7g, with the lateral chain in the para position of the phenyl ring, possessed an optimal docking pose and can perfectly fit into the catalytic active site (CAS) and peripheral anionic site (PAS), simultaneously, and, consequently, exhibited higher inhibitory potency than 7b that bears the same lateral chain as 7g, but in the ortho position of the phenyl ring. [Copyright &y& Elsevier]

Abstract: Alzhemier''s disease (AD) is a common form of dementia in the ageing population which is characterized by depositions of amyloids and a cholinergic neurotransmission deficit in the brain. Current therapeutic intervention for AD is primarily based on the inhibition of brain acetylcholinesterase (AChE) to restore the brain acetylcholine level. Cryptotanshinone (CT) and dihydrotanshinone (DT) were diterpenoids extracted from Salvia miltiorrhiza Bge. having anti-cholinesterase activity. Here we characterized the inhibition property of these two diterpenoids towards human AChE and butyrylcholinesterase (BChE). Both CT and DT were found to be mixed non-competitive inhibitors for human AChE and an uncompetitive inhibitor for human BChE. The docking analyses of CT and DT into the active sites of both cholinesterases indicate that they interact with the allosteric site inside the active-site gorge mainly by hydrophobic interactions. [Copyright &y& Elsevier]

Glycogen synthase kinase-3α and -3β (GSK-3α and -3β) are multi-substrate, serine/threonine-specific kinases that can phosphorylate microtubule-associated protein tau and other neuronal proteins. In this study, the expression level and mRNA distribution of two GSK-3 isoforms, GSK-3α and -3β in mice were investigated. Northern blot analyses indicated that GSK-3α mRNA is encoded by a 2.5-kb transcript in adult tissues, whereas a 4.1-kb transcript was found in neonatal tissues. The GSK-3β mRNA is encoded by a 1.6-kb transcript in the testis and a 7.6-kb transcript in the brain, and in many other adult tissues, but not neonatal tissues. Western blot analyses demonstrated that GSK-3β protein was mainly expressed in the brain and heart, whereas GSK-3α was highly expressed in the brain, heart, and testis. A non-radioactive in situ hybridization study using specific digoxigenin-labeled RNA probes showed that GSK-3α and -3β mRNAs were found in many brain regions, and were especially abundant in the hippocampus, cerebral cortex, and the Purkinje cells of the cerebellum. This implies the importance of GSK-3α and -3β for brain function. The differential expression of GSK-3α and -3β mRNAs as well as proteins in other tissues indicate that they play different roles in cellular functions and the developmental process. [Copyright &y& Elsevier]