New spirocyclic Δ²-isoxazoline derivatives related to selective agonists of α7 neuronal nicotinic acetylcholine receptors.
A set of structural analogues of spirocyclic quinuclidinyl-Δ(2)-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 Δ(2)-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the α7 nAChRs (K(i) = 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.
Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. clelia.dallanoce@unimi.it
Clelia
C
Dallanoce
Fabio
F
Frigerio
Giovanni
G
Grazioso
Carlo
C
Matera
Giacomo Luca
GL
Visconti
Marco
M
De Amici
Luca
L
Pucci
Francesco
F
Pistillo
Sergio
S
Fucile
Cecilia
C
Gotti
Francesco
F
Clementi
Carlo
C
De Micheli
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2