Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors

Gabriele Murineddu, Cecilia Gotti, Battistina Asproni, Paola Corona, Katiuscia Martinello, Simona Plutino, Sergio Fucile, Veronika Temml, Milena Moretti, Paola Viani, Daniela Schuster, Sandra Piras, Francesco Deligia, Gerard A Pinna

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Abstract

We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with α4β2Ki value of 10 pM and a very high α7/α4β2 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for α4β2 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.

Original languageEnglish
Pages (from-to)51-61
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume180
DOIs
Publication statusE-pub ahead of print - Jul 5 2019

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Murineddu, G., Gotti, C., Asproni, B., Corona, P., Martinello, K., Plutino, S., Fucile, S., Temml, V., Moretti, M., Viani, P., Schuster, D., Piras, S., Deligia, F., & Pinna, G. A. (2019). Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors. European Journal of Medicinal Chemistry, 180, 51-61. https://doi.org/10.1016/j.ejmech.2019.06.079