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

Winnie Deuther-Conrad; Dirk Schepmann; Isabel Iriepa; Francisco López-Muñoz; Mourad Chioua; Bernhard Wünsch; Abdelouahid Samadi; José Marco-Contelles

doi:10.3390/ijms26031266

2-{N-[ω-(1-Benzylpiperidin-4-yl)alkyl]amino}-6-[(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitriles Showing High Affinity for σ_1/2 Receptors

Winnie Deuther-Conrad, Dirk Schepmann, Isabel Iriepa, Francisco López-Muñoz, Mourad Chioua, Bernhard Wünsch, Abdelouahid Samadi, José Marco-Contelles

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

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 (K_i(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.

Original language	English
Article number	1266
Journal	International journal of molecular sciences
Volume	26
Issue number	3
DOIs	https://doi.org/10.3390/ijms26031266
Publication status	Published - Feb 2025

Keywords

ADME
computational chemistry
docking
multifunctional pyridines
sigma receptors

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

Access to Document

10.3390/ijms26031266

Cite this

Deuther-Conrad, W., Schepmann, D., Iriepa, I., López-Muñoz, F., Chioua, M., Wünsch, B., Samadi, A., & Marco-Contelles, J. (2025). 2-{N-[ω-(1-Benzylpiperidin-4-yl)alkyl]amino}-6-[(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitriles Showing High Affinity for σ_1/2 Receptors. International journal of molecular sciences, 26(3), Article 1266. https://doi.org/10.3390/ijms26031266

Deuther-Conrad, W, Schepmann, D, Iriepa, I, López-Muñoz, F, Chioua, M, Wünsch, B, Samadi, A & Marco-Contelles, J 2025, '2-{N-[ω-(1-Benzylpiperidin-4-yl)alkyl]amino}-6-[(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitriles Showing High Affinity for σ_1/2 Receptors', International journal of molecular sciences, vol. 26, no. 3, 1266. https://doi.org/10.3390/ijms26031266

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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.",

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