Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors
| Autor: | Fabio Frigerio, Carlo De Micheli, Sergio Fucile, Clelia Dallanoce, Pietro Magrone, Vanessa Piccari, Francesco Clementi, Marco De Amici, Karla Frydenvang, Giovanni Grazioso, Cecilia Gotti, Carlo Matera, Luca Pucci |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
alpha7 Nicotinic Acetylcholine Receptor
Stereochemistry Molecular Conformation Receptors Nicotinic Biochemistry α7 nicotinic acetylcholine receptor Catalytic Domain Drug Discovery Potency Homomeric Animals Humans Computer Simulation Spiro Compounds Nicotinic Agonists General Pharmacology Toxicology and Pharmaceutics Receptor Acetylcholine receptor Pharmacology alpha 7 agonists electrophysiological assays delta(2)-isoxazoline derivatives neuronal nicotinic acetylcholine receptors x-ray crystallography Aza Compounds Binding Sites Chemistry Organic Chemistry Stereoisomerism Isoxazoles Cycloaddition Rats Nicotinic agonist Drug Design Molecular Medicine Enantiomer |
| Zdroj: | ChemMedChem. 6(5) |
| ISSN: | 1860-7187 |
| Popis: | A set of racemic spirocyclic quinuclidinyl-Δ(2)-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ(2) -Isoxazolines 3 a (3-Br), 6 a (3-OMe), 5 a (3-Ph), 8 a (3-OnPr), and 4 a (3-Me) were the ligands with the highest affinity for the α7 subtype (K(i) values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 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 6 a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6 a was found to be the eutomer, with K(i) values of 4.6 and 48.7 nM against rat and human α7 receptors, respectively. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text