%0 Journal Article %1 Dallanoce2007 %A Dallanoce, C. %A Frigerio, F. %A Amici, M. De %A Dorsch, S. %A Klotz, K. N. %A Micheli, C. De %D 2007 %J Bioorg Med Chem %K Adenylate Animals Assay CHO Cell Cricetinae Cricetulus Cyclase/metabolism Humans Indicators Isoxazoles/*chemical Magnetic Membrane Radioligand Reagents Relationship Resonance Spectroscopy Stereoisomerism Structure-Activity and beta-2/*drug effects synthesis/*pharmacology Receptor Adrenergic %N 7 %P 2533-43 %T Novel chiral isoxazole derivatives: synthesis and pharmacological characterization at human beta-adrenergic receptor subtypes %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17303428 %V 15 %X Isoxazole derivative (+/-)-4 and the three pairs of stereoisomeric 3-bromo-isoxazolyl amino alcohols (S,R)-(-)-7a/(R,R)-(+)-7b, (S,R)-(-)-8a/(R,R)-(+)-8b, and (S,R)-(-)-9a/(R,R)-(+)-9b were synthesized and assayed for their affinity and efficacy at human beta(1)-, beta(2)-, and beta(3)-adrenergic receptors (beta-ARs) in membranes from Chinese hamster ovary (CHO) cells stably transfected with the respective receptor subtype. Whereas derivative (+/-)-4 did not bind at all three beta-ARs, stereoisomers (S,R)-7a-(S,R)-9a behaved as high-affinity ligands at beta(1)- and, particularly, at beta(2)-ARs (K(i) 2.82-66.7 nM). The K(i) values of isomers (R,R)-7b-(R,R)-9b at beta(1)- and beta(2)-subtypes were about 30-100 times higher than those of their (S,R)-7a-9a counterparts, indicating a sizable stereochemical effect. The affinity at beta(3)-ARs was negligible for all the investigated compounds. When submitted to a functional assay, the three stereoisomeric pairs showed a comparable pattern of efficacy at all three beta-AR subtypes. The highest value of efficacy (75-90%) was observed at beta(2)-ARs, whereas all compounds behaved as partial agonists (30-60%) at the beta(3)-subtype. The lowest degree of efficacy (15-35%) was found at beta(1)-ARs. The affinity/efficacy profile of the derivatives under study has been compared with that of the two model compounds, Broxaterol (+/-)-1 and BRL 37344 (+/-)-6.

@article{Dallanoce2007, abstract = {Isoxazole derivative (+/-)-4 and the three pairs of stereoisomeric 3-bromo-isoxazolyl amino alcohols (S,R)-(-)-7a/(R,R)-(+)-7b, (S,R)-(-)-8a/(R,R)-(+)-8b, and (S,R)-(-)-9a/(R,R)-(+)-9b were synthesized and assayed for their affinity and efficacy at human beta(1)-, beta(2)-, and beta(3)-adrenergic receptors (beta-ARs) in membranes from Chinese hamster ovary (CHO) cells stably transfected with the respective receptor subtype. Whereas derivative (+/-)-4 did not bind at all three beta-ARs, stereoisomers (S,R)-7a-(S,R)-9a behaved as high-affinity ligands at beta(1)- and, particularly, at beta(2)-ARs (K(i) 2.82-66.7 nM). The K(i) values of isomers (R,R)-7b-(R,R)-9b at beta(1)- and beta(2)-subtypes were about 30-100 times higher than those of their (S,R)-7a-9a counterparts, indicating a sizable stereochemical effect. The affinity at beta(3)-ARs was negligible for all the investigated compounds. When submitted to a functional assay, the three stereoisomeric pairs showed a comparable pattern of efficacy at all three beta-AR subtypes. The highest value of efficacy (75-90%) was observed at beta(2)-ARs, whereas all compounds behaved as partial agonists (30-60%) at the beta(3)-subtype. The lowest degree of efficacy (15-35%) was found at beta(1)-ARs. The affinity/efficacy profile of the derivatives under study has been compared with that of the two model compounds, Broxaterol [(+/-)-1] and BRL 37344 [(+/-)-6].}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Dallanoce, C. and Frigerio, F. and Amici, M. De and Dorsch, S. and Klotz, K. N. and Micheli, C. De}, biburl = {https://www.bibsonomy.org/bibtex/2b986b3aaa971f9d08ad5329f04c4d488/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {4ab7d27cfb7cd00b5291a0beca61fc02}, intrahash = {b986b3aaa971f9d08ad5329f04c4d488}, issn = {0968-0896 (Print) 0968-0896 (Linking)}, journal = {Bioorg Med Chem}, keywords = {Adenylate Animals Assay CHO Cell Cricetinae Cricetulus Cyclase/metabolism Humans Indicators Isoxazoles/*chemical Magnetic Membrane Radioligand Reagents Relationship Resonance Spectroscopy Stereoisomerism Structure-Activity and beta-2/*drug effects synthesis/*pharmacology Receptor Adrenergic}, month = {Apr 1}, note = {Dallanoce, Clelia Frigerio, Fabio De Amici, Marco Dorsch, Sandra Klotz, Karl-Norbert De Micheli, Carlo Research Support, Non-U.S. Gov't England Bioorganic \& medicinal chemistry Bioorg Med Chem. 2007 Apr 1;15(7):2533-43. Epub 2007 Feb 2.}, number = 7, pages = {2533-43}, shorttitle = {Novel chiral isoxazole derivatives: synthesis and pharmacological characterization at human beta-adrenergic receptor subtypes}, timestamp = {2010-12-14T18:22:39.000+0100}, title = {Novel chiral isoxazole derivatives: synthesis and pharmacological characterization at human beta-adrenergic receptor subtypes}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17303428}, volume = 15, year = 2007 }