TY - JOUR
T1 - New spirocyclic Δ2-isoxazoline derivatives related to selective agonists of α7 neuronal nicotinic acetylcholine receptors
AU - Dallanoce, Clelia
AU - Frigerio, Fabio
AU - Grazioso, Giovanni
AU - Matera, Carlo
AU - Visconti, Giacomo Luca
AU - De Amici, Marco
AU - Pucci, Luca
AU - Pistillo, Francesco
AU - Fucile, Sergio
AU - Gotti, Cecilia
AU - Clementi, Francesco
AU - De Micheli, Carlo
PY - 2011/12
Y1 - 2011/12
N2 - A set of structural analogues of spirocyclic quinuclidinyl- Δ2-isoxazolines, characterized as potent and selective α7 nicotinic agonists, was prepared and assayed for binding affinity at α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a-3c, 4a-4c, 5a-5c, 6a-6c, and 7a-7c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the α7 subtype when compared with their model compounds. Solely Δ2-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the α7 nAChRs (Ki = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy α7 vs. α4β2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.
AB - A set of structural analogues of spirocyclic quinuclidinyl- Δ2-isoxazolines, characterized as potent and selective α7 nicotinic agonists, was prepared and assayed for binding affinity at α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a-3c, 4a-4c, 5a-5c, 6a-6c, and 7a-7c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the α7 subtype when compared with their model compounds. Solely Δ2-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the α7 nAChRs (Ki = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy α7 vs. α4β2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.
KW - α7 Selective nicotinic ligands
KW - Binding affinity
KW - Cycloaddition reaction
KW - Electrophysiological assays
KW - Molecular modeling
KW - Neuronal nicotinic acetylcholine receptors
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U2 - 10.1016/j.ejmech.2011.09.028
DO - 10.1016/j.ejmech.2011.09.028
M3 - Article
C2 - 22014558
AN - SCOPUS:80955131247
VL - 46
SP - 5790
EP - 5799
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 12
ER -