Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Delta2-isoxazoline derivatives as potent and selective agonists of alpha7 nicotinic acetylcholine receptors.

A set of racemic spirocyclic quinuclidinyl-D2-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (a7) and heteromeric (a4b2) nicotinic acetylcholine receptors. D2-Isoxazolines 3a (3-Br), 6a (3-OMe), 5a (3-Ph), 8a (3-OnPr), and 4a (3-Me) were the ligands with the highest affinity for the a7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 nm, respectively), and showed excellent a7 versus a4b2 subtype selectivity. These compounds, tested in electrophysiological experiments against human a7 and a4b2 receptors stably expressed in cell lines, behaved as partial a7 agonists with varying levels of potency. The two enantiomers of ()-3-methoxy-1-oxa-2,7-diaza-7,10- ethanospiro[4.5]dec-2-ene sesquifumarate 6a were prepared using (+)-dibenzoyl-l- or ()-dibenzoyl-d-tartaric acid as resolving agents. Enantiomer (R)-()-6a was found to be the eutomer, with Ki values of 4.6 and 48.7 nm against rat and human a7 receptors, respectively.