Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes
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...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2010-06, Vol.18 (12), p.4498-4508 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Dallanoce, Clelia Frigerio, Fabio Martelli, Giuliana Grazioso, Giovanni Matera, Carlo Pomè, Diego Yuri Pucci, Luca Clementi, Francesco Gotti, Cecilia De Amici, Marco |
| description | 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. |
| doi_str_mv | 10.1016/j.bmc.2010.04.065 |
| format | Article |
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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.</description><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2010.04.065</identifier><identifier>PMID: 20478710</identifier><language>eng</language><publisher>England</publisher><subject>Alkaloids - chemistry ; alpha7 Nicotinic Acetylcholine Receptor ; Animals ; Azocines - chemistry ; Binding Sites ; Bridged Bicyclo Compounds, Heterocyclic - chemistry ; Heterocyclic Compounds, 3-Ring - chemical synthesis ; Heterocyclic Compounds, 3-Ring - chemistry ; Heterocyclic Compounds, 3-Ring - pharmacology ; Isoxazoles - chemical synthesis ; Isoxazoles - chemistry ; Isoxazoles - pharmacology ; Ligands ; Models, Molecular ; Neurons - metabolism ; Protein Binding ; Quinolizines - chemistry ; Rats ; Receptors, Nicotinic - chemistry ; Receptors, Nicotinic - metabolism</subject><ispartof>Bioorganic & medicinal chemistry, 2010-06, Vol.18 (12), p.4498-4508</ispartof><rights>Copyright 2010 Elsevier Ltd. 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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.</description><subject>Alkaloids - chemistry</subject><subject>alpha7 Nicotinic Acetylcholine Receptor</subject><subject>Animals</subject><subject>Azocines - chemistry</subject><subject>Binding Sites</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemistry</subject><subject>Heterocyclic Compounds, 3-Ring - chemical synthesis</subject><subject>Heterocyclic Compounds, 3-Ring - chemistry</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacology</subject><subject>Isoxazoles - chemical synthesis</subject><subject>Isoxazoles - chemistry</subject><subject>Isoxazoles - pharmacology</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Neurons - metabolism</subject><subject>Protein Binding</subject><subject>Quinolizines - chemistry</subject><subject>Rats</subject><subject>Receptors, Nicotinic - chemistry</subject><subject>Receptors, Nicotinic - metabolism</subject><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMtOwzAQRS0kREvhA9gg74BFgh95lR0qT6mCDawj25lQV44dYqdq-CF-kwBFrEZ35sy90kXohJKYEppdrmPZqJiRUZMkJlm6h6Y0yZKI8zmdoEPv14QQlszpAZowkuRFTskUfT65DRgcOq0GZbTCN2CCOGcXkfZuKz6c0RawsBXmkdu6iEUNhNVg_s_VN1BBpzci6A34K-wHG1bgtf_5k9qOyBsWda2tDgMWAVvoO2eFwVYrF8a1wkJBGIxa_QZ2oKANrsO-l2FowR-h_VoYD8e7OUOvd7cvi4do-Xz_uLheRi2jJEQJr1MuKgDOE5WCyivIRZoUeQ6CE654wTMlGQGRykJyxYoik5kalQRRZ5LP0Nmvb9u59x58KBvtFRgjLLjel_loPJZHyEie7sheNlCVbacb0Q3lX7f8C-c7f-U</recordid><startdate>20100615</startdate><enddate>20100615</enddate><creator>Dallanoce, Clelia</creator><creator>Frigerio, Fabio</creator><creator>Martelli, Giuliana</creator><creator>Grazioso, Giovanni</creator><creator>Matera, Carlo</creator><creator>Pomè, Diego Yuri</creator><creator>Pucci, Luca</creator><creator>Clementi, Francesco</creator><creator>Gotti, Cecilia</creator><creator>De Amici, Marco</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20100615</creationdate><title>Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes</title><author>Dallanoce, Clelia ; 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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.</abstract><cop>England</cop><pmid>20478710</pmid><doi>10.1016/j.bmc.2010.04.065</doi><tpages>11</tpages></addata></record> |
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| subjects | Alkaloids - chemistry alpha7 Nicotinic Acetylcholine Receptor Animals Azocines - chemistry Binding Sites Bridged Bicyclo Compounds, Heterocyclic - chemistry Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Isoxazoles - chemical synthesis Isoxazoles - chemistry Isoxazoles - pharmacology Ligands Models, Molecular Neurons - metabolism Protein Binding Quinolizines - chemistry Rats Receptors, Nicotinic - chemistry Receptors, Nicotinic - metabolism |
| title | Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes |
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