Synthesis of Bridgehead-Substituted Azabicyclo[2.2.1]heptane and -[3.3.1]nonane Derivatives for the Elaboration of α7 Nicotinic Ligands

• Published in: Journal of organic chemistry 2011-10, Vol.76 (20), p.8336-8346
• Main Authors: Slowinski, Franck, Ben Ayad, Omar, Vache, Julien, Saady, Mourad, Leclerc, Odile, Lochead, Alistair
• Format: Article
• Language: English
• Subjects: Alkanes - chemistry; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Azabicyclo Compounds - chemical synthesis; Azabicyclo Compounds - metabolism; Azabicyclo Compounds - pharmacology; Chemistry; Chemistry, Pharmaceutical - methods; Chlorides - chemistry; Exact sciences and technology; Halogenation; Heptanes - chemistry; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Ligands; Magnetic Resonance Spectroscopy; Nicotinic Agonists - chemical synthesis; Nicotinic Agonists - metabolism; Nicotinic Agonists - pharmacology; Organic chemistry; Preparations and properties; Protons; Pyridines - chemistry; Receptors, Nicotinic - metabolism; Schizophrenia - drug therapy; Schizophrenia - metabolism; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo201501f

Azabicyclo[2.2.1]heptane and -[3.3.1]nonane scaffolds (X = Cl, Br) containing a pyridinyl substituent at the bridgehead position were prepared via two complementary chemical pathways, either by the transformation of a methoxy group into a synthetically valuable chlorine atom at the C-6 position of the pyridine moiety or by means of a regioselective C-6 deprotonation/halogenation process of the pyridine moiety exemplified by chlorination or bromination. These newly generated scaffolds were then engaged in Suzuki–Miyaura coupling reactions to provide α7 nicotinic ligands. Both chemical series were evaluated in vitro for their affinity at α7 nicotinic receptors, revealing nanomolar potency with significant selectivity over the α4β2 nicotinic subtype. These approaches offer a general access to these α7 nicotinic scaffolds and ligands.