title: Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Milan, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.forename: Pietro
authors.initials: P
authors.lastname: Magrone
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.forename: Fabio
authors.initials: F
authors.lastname: Frigerio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.forename: Vanessa
authors.initials: V
authors.lastname: Piccari
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Clementi
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C560362:3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro(4.5)dec-2-ene; D001372:Aza Compounds; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor