Pyridinyl- and pyridazinyl-3,6-diazabicyclo[3.1.1]heptane-anilines: Novel selective ligands with subnanomolar affinity for α4β2 nACh receptors

• Published in: European journal of medicinal chemistry Vol. 152; pp. 401 - 416
• Main Authors: Deligia, Francesco, Murineddu, Gabriele, Gotti, Cecilia, Ragusa, Giulio, Fasoli, Francesca, Sciaccaluga, Miriam, Plutino, Simona, Fucile, Sergio, Loriga, Giovanni, Asproni, Battistina, Pinna, Gerard A.
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 25.05.2018
• Subjects: 3,6-diazabicyclo[3.1.1]heptanes; Agonism; Neuronal nicotinic acetylcholine receptors; Synthesis; α4β2 selectivity; 3,6-diazabicyclo[3.1.1]heptanes; Neuronal nicotinic acetylcholine receptors; Agonism; α4β2 selectivity; Synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.04.026

The cholinergic pathways in the central nervous system (CNS) of animals and humans are important for cognitive and behavioural functions. Until a few years ago, it was thought that the key molecules transducing the cholinergic message were the metabotropic muscarinic receptors, but it is now known that ionotropic neuronal nicotinic receptors (nAChRs) are also involved. Based on recent studies, we prepared a small library of novel 3-substituted-3,6-diazabicyclo [3.1.1]heptanes, whose binding activity and functionality have been assayed. Among the synthesized compounds, the 3-(anilino)pyridine series resulted in the most interesting compounds with α4β2Ki values ranging from 0.0225 nM (12g) to 2.06 nM (12o). [Display omitted] •Synthesis of novel heteroaryl-3,6-diazabicyclo [3.1.1]heptane-anilines.•Binding activity for neuronal acetylcholine receptor subtypes α4β2, α7 and α3β4.•Intrinsic α4β2 receptor mediated activity.