Design, Synthesis, and Pharmacological Characterization of Novel Spirocyclic Quinuclidinyl-Delta(2)-Isoxazoline Derivatives as Potent and Selective Agonists of alpha 7 Nicotinic Acetylcholine Receptors

作者：Dallanoce Clelia^*; Magrone Pietro; Matera Carlo; Frigerio Fabio; Grazioso Giovanni; De Amici Marco; Fucile Sergio; Piccari Vanessa; Frydenvang Karla; Pucci Luca; Gotti Cecilia; Clementi Francesco; De Micheli Carlo

来源：ChemMedChem, 2011, 6(5): 889-903.

DOI：10.1002/cmdc.201000514

• electrophysiological assays
• neuronal nicotinic acetylcholine receptors
• X-ray crystallography
• alpha 7 agonists
• Delta(2)-isoxazoline derivatives

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.

• 出版日期2011-5-2