# 2-{N-[ω-(1-Benzylpiperidin-4-yl)alkyl]amino}-6-[(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitriles Showing High Affinity for σ1/2 Receptors

## TL;DR

This paper reports a new compound with high affinity for sigma receptors and strong activity against cholinesterase enzymes, which could be useful for treating neurological disorders.

## Contribution

The study introduces a novel pyridine-based compound with potent dual-target activity and high sigma-1 receptor selectivity.

## Key findings

- Compound 5 shows potent inhibition of acetylcholinesterase (IC50 = 13 nM) and butyrylcholinesterase (IC50 = 3.1 µM).
- It exhibits high σ1R affinity (Ki = 1.45 nM) and 290-fold selectivity over σ2R.
- Molecular modeling supports the compound's structural features responsible for its activity.

## Abstract

Sigma receptors (σRs) 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) (IC50 = 13 nM) and butyrylcholinesterase (BuChE) (IC50 = 3.1 µM), exhibiting high σ1R affinity (Ki(hσ1R) = 1.45 nM) and 290-fold selectivity over the σ2R 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.