A set of racemic spirocyclic quinuclidinyl-Delta(2)-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (alpha 7) and heteromeric (alpha 4 beta 2) nicotinic acetylcholine receptors. Delta(2)-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 alpha 7 subtype (K-i values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 nm, respectively), and showed excellent alpha 7 versus alpha 4 beta 2 subtype selectivity. These compounds, tested in electrophysiological experiments against human alpha 7 and alpha 4 beta 2 receptors stably expressed in cell lines, behaved as partial alpha 7 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 K-i values of 4.6 and 48.7 nm against rat and human alpha 7 receptors, respectively.
Design, Synthesis, and Pharmacological Characterization of Novel Spirocyclic Quinuclidinyl-Delta(2)-Isoxazoline Derivatives as Potent and Selective Agonists of alpha 7 Nicotinic Acetylcholine Receptors / C., Dallanoce; P., Magrone; C., Matera; F., Frigerio; G., Grazioso; M., De Amici; Fucile, Sergio; Piccari, Vanessa; K., Frydenvang; L., Pucci; C., Gotti; F., Clementi; C., De Micheli. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 6:(2011), pp. 889-903. [10.1002/cmdc.201000514]