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Open AccessArticle

Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters

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Departamento de Química Orgánica y Fisicoquímica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380492 Santiago, Chile
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Departamento de Ciencias Químicas y Recursos Naturales, Facultad de Ingeniería y Ciencias, Universidad de la Frontera, 4811230 Temuco, Chile
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Center of Excellence in Biotechnology Research Applied to the Environment, Universidad de La Frontera, 4811230 Temuco, Chile
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Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, 9170022 Santiago, Chile
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Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, 3467987 Sede Talca, Chile
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Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 3340000 Talca, Chile
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Escuela de Ingeniería Civil en Bioinformática, Universidad de Talca, Av. Lircay 3340000 Talca, Chile
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Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, 2360102 Valparaíso, Chile
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Departamento de Química Inorgánica and Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380492 Santiago, Chile
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Authors to whom correspondence should be addressed.
Molecules 2019, 24(20), 3808; https://doi.org/10.3390/molecules24203808
Received: 10 September 2019 / Revised: 7 October 2019 / Accepted: 20 October 2019 / Published: 22 October 2019
(This article belongs to the Section Medicinal Chemistry)
Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 μM for h-DAT and 0.031 ± 0.006 μM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 μM for α4β2 nAChR and 0.075 ± 0.009 μM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4β2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT. View Full-Text
Keywords: nAChR; DAT; allosteric modulators; SERT; α4β2; allosteric modulators; affinity nAChR; DAT; allosteric modulators; SERT; α4β2; allosteric modulators; affinity
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González-Gutiérrez, J.P.; Pessoa-Mahana, H.A.; Iturriaga-Vásquez, P.E.; Reyes-Parada, M.I.; Guerra-Díaz, N.E.; Hodar-Salazar, M.; Viscarra, F.; Paillali, P.; Núñez-Vivanco, G.; Lorca-Carvajal, M.A.; Mella-Raipán, J.; Zúñiga, M.C. Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters. Molecules 2019, 24, 3808.

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