Julien Vache

Synthesis of New Bridgehead Substituted Azabicyclo-[2.2.1]heptane and -[3.3.1]nonane Derivatives as Potent and Selective α7 Nicotinic Ligands

New azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives containing a pyridinyl substituent at the bridgehead position have been synthesized via an efficient ten chemical steps pathway. Both chemical series were then evaluated in vitro for their affinity at α7 nicotinic receptors revealing nanomolar potency with notably excellent selectivity over the α4β2 nicotinic subtype.

Synthesis of bridgehead-substituted azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives for the elaboration of α7 nicotinic ligands.

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.