title: Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes.
abstract: A group of novel tricyclic Delta(2)-isoxazolines (4b, 5b, 7a-b, and 8a-b) and 3-oxo-isoxazolidines (6a-b and 9a-b), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at alpha4beta2 and alpha7 neuronal acetylcholine receptors (nAChRs). The results of competition binding experiments indicated for the new derivatives a reduction of the affinity at the alpha4beta2 subtype in comparison with the reference molecules, coupled with an overall negligible affinity at the alpha7 subtype. The binding mode of the bromo-Delta(2)-isoxazolines 4b and 7b, which were the highest affinity ligands in the series (K(i)=0.92 and 0.75 microM, respectively), was analyzed by applying a recently developed model of the alpha4beta2 nAChRs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. clelia.dallanoce@unimi.it
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.forename: Fabio
authors.initials: F
authors.lastname: Frigerio
authors.forename: Giuliana
authors.initials: G
authors.lastname: Martelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.forename: Diego Yuri
authors.initials: DY
authors.lastname: Pomè
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.forename: Francesco
authors.initials: F
authors.lastname: Clementi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
mesh_terms: D000470:Alkaloids / Q000737:chemistry; D000818:Animals; D001392:Azocines / Q000737:chemistry; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D011807:Quinolizines / Q000737:chemistry; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006575:Heterocyclic Compounds, 3-Ring; D007555:Isoxazoles; D008024:Ligands; D011807:Quinolizines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C552773:3-bromo-5-oxa-4,10-diazatricyclo(6.3.1.0(2,6))dodec-3-ene; C552774:5-bromo-3-oxa-4,11-diazatricyclo(6.2.1.0(2,6))undec-4-ene; C579165:Chrna7 protein, rat; C418212:ferruginine; C403531:nicotinic receptor alpha4beta2; C004712:cytisine; D000093843:Quinolizidine Alkaloids