1,8-Naphthyridine derivatives as Cholinesterases Inhibitors and Cell Ca2+ Regulators, a Multitarget Strategy for Alzheimer's Disease

Javier      Egea; Cristobal      de los Rios

Abstract

The synthesis and the pharmacological evaluation of 1,8-naphthyridine derivatives and related compounds as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as voltage-dependant Ca2+ channels (VDCC) modulators of are summarized. These compounds are closely related to the anticholinesterasic tacrine and the well-known Ca2+-antagonists 1,4-dihydropyridines. They were obtained from polyfunctionalized 2-amino-3-cyanoheterocycles via Friedlander-type reaction with selected cycloalkanones. Most of the compounds showed moderate inhibitory activity of cholinesterases, with selectivity to the AChE inhibition, and blocked Ca2+ channels, preferentially the Lsubtype, when a 4-aryl-1,4-DHP-like moiety were present in its chemical structure. Taking into account that the regulation of Ca2+ entry to cells has been described to play a key role in cell death/survival processes, some of them were studied as cytoprotective agentes against different toxic stimuli. Specifically, the 1,8-naphthyridine derivative 30 was described to exert a tiny positive effect on Ca2+ entry to cells, as single cell, isolated organ, and 45Ca2+ uptake experiments showed. This slight “Ca2+-promoter” behavior was related to its cytoprotective effect against several toxic stimuli, as Ca2+- chelating and antiapoptotic protein Bcl-2 was overexpressed in bovine chromaffin cells preincubated with 30. In fact, the relationship between small elevations of [Ca2+]c and neuroprotection has been deeply studied by our group and others, concluding that a huge blockade of Ca2+ entry does not have to generate neuroprotection, but the precise regulation, up or down, of such [Ca2+] concentrations.

Keywords: Acetylcholinesterase, alzheimer's disease, drug discovery, friedlander reaction, 1, 8-naphthyridines, voltagedependant calcium channels, pharmacological evaluation, acetylcholinesterase (AChE), voltage-dependant Ca2+, antiapoptotic protein, inhibiting acetylcholinesterase(AChE), polyfunctionalized 4H-pyrans, amyloid fibrils aggregation, cycloalkanone, aluminum trichloride