Deuther-Conrad_2025_Int.J.Mol.Sci_26_

Sigma receptors (sigmaRs) represent very attractive biological targets for the development of potential agents for the treatment of several neurological disorders. In the search for new small molecule drugs against neuropathic pain, we identified 2-{[2-(1-benzylpiperidin-4-yl)ethyl]amino}-6-[methyl(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitrile (5) as a polyfunctionalized small pyridine with potent dual-target activities against acetylcholinesterase (AChE) (IC(50) = 13 nM) and butyrylcholinesterase (BuChE) (IC(50) = 3.1 microM), exhibiting high sigma(1)R affinity (K(i)(hsigma(1)R) = 1.45 nM) and 290-fold selectivity over the sigma(2)R subtype. These results are in good agreement with those found in the molecular modeling of compound 5. This is possibly due to the preferred combination in this molecule of a linker n = 2 connecting the N-Bn-piperidine motif to the C2 pyridine, without a phenyl group at C4, and a N-Me-substituted propargyl amine in the chain located at C6.