1,8-Naphthyridine derivatives as cholinesterases inhibitors and cell Ca2+ regulators, a multitarget strategy for Alzheimer's disease.

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 Ca(2+) channels (VDCC) modulators of are summarized. These compounds are closely related to the anticholinesterasic tacrine and the well-known Ca(2+)-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 Ca(2+) channels, preferentially the L-subtype, when a 4-aryl-1,4-DHP-like moiety were present in its chemical structure. Taking into account that the regulation of Ca(2+) 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 Ca(2+) entry to cells, as single cell, isolated organ, and (45)Ca(2+) uptake experiments showed. This slight "Ca(2+)-promoter" behavior was related to its cytoprotective effect against several toxic stimuli, as Ca(2+)-chelating and antiapoptotic protein Bcl-2 was overexpressed in bovine chromaffin cells preincubated with 30. In fact, the relationship between small elevations of [Ca(2+)](c) and neuroprotection has been deeply studied by our group and others, concluding that a huge blockade of Ca(2+) entry does not have to generate neuroprotection, but the precise regulation, up or down, of such [Ca(2+)] concentrations.