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Article

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

by
Winnie Deuther-Conrad
1,
Dirk Schepmann
2,
Isabel Iriepa
3,4,
Francisco López-Muñoz
5,6,7,
Mourad Chioua
8,
Bernhard Wünsch
2,
Abdelouahid Samadi
9,* and
José Marco-Contelles
8,10,*
1
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, D-04318 Leipzig, Germany
2
Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, D-48149 Münster, Germany
3
Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. del Río” (IQAR), Universidad de Alcalá, Alcalá de Henares, 28805 Madrid, Spain
4
Grupo DISCOBAC, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 28805 Madrid, Spain
5
Faculty of Health Sciences–HM Hospitals, University Camilo José Cela, 28692 Madrid, Spain
6
HM Hospitals Health Research Institute, 28015 Madrid, Spain
7
Neuropsychopharmacology Unit, “Hospital 12 de Octubre” Research Institute, 28041 Madrid, Spain
8
Institute of General Organic Chemistry (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain
9
Department of Chemistry, College of Science, United Arab Emirates University, Al Ain 15551, United Arab Emirates
10
Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, 46010 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(3), 1266; https://doi.org/10.3390/ijms26031266
Submission received: 19 December 2024 / Revised: 29 January 2025 / Accepted: 30 January 2025 / Published: 31 January 2025
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
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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.
Keywords: ADME; computational chemistry; docking; multifunctional pyridines; sigma receptors ADME; computational chemistry; docking; multifunctional pyridines; sigma receptors

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MDPI and ACS Style

Deuther-Conrad, W.; Schepmann, D.; Iriepa, I.; López-Muñoz, F.; Chioua, M.; Wünsch, B.; Samadi, A.; Marco-Contelles, J. 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. Int. J. Mol. Sci. 2025, 26, 1266. https://doi.org/10.3390/ijms26031266

AMA Style

Deuther-Conrad W, Schepmann D, Iriepa I, López-Muñoz F, Chioua M, Wünsch B, Samadi A, Marco-Contelles J. 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. International Journal of Molecular Sciences. 2025; 26(3):1266. https://doi.org/10.3390/ijms26031266

Chicago/Turabian Style

Deuther-Conrad, Winnie, Dirk Schepmann, Isabel Iriepa, Francisco López-Muñoz, Mourad Chioua, Bernhard Wünsch, Abdelouahid Samadi, and José Marco-Contelles. 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 σ1/2 Receptors" International Journal of Molecular Sciences 26, no. 3: 1266. https://doi.org/10.3390/ijms26031266

APA Style

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 σ1/2 Receptors. International Journal of Molecular Sciences, 26(3), 1266. https://doi.org/10.3390/ijms26031266

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