Synthesis of enantiopure Delta2-isoxazoline derivatives and evaluation
of their affinity and efficacy profiles at human beta-adrenergic
receptor subtypes
C. Dallanoce, G. Meroni, M. Amici, C. Hoffmann, K. Klotz, and C. Micheli. Bioorg Med Chem, 14 (13):
4393-401(July 2006)Dallanoce, Clelia Meroni, Giuseppe De Amici, Marco Hoffmann, Carsten
Klotz, Karl-Norbert De Micheli, Carlo Research Support, Non-U.S.
Gov't England Bioorganic & medicinal chemistry Bioorg Med Chem.
2006 Jul 1;14(13):4393-401. Epub 2006 Mar 10..
Abstract
The new enantiomerically pure 3-substituted-Delta(2)-isoxazolin-5-yl-ethanolamines
(+)-6a/(-)-6b, (-)-6a/(+)-6b, and (+)-7a/(-)-7b, prepared via a 1,3-dipolar
cycloaddition-based approach, were tested for their affinity at human
beta(1)-, beta(2)-, and beta(3)-adrenergic receptor (beta-AR) subtypes
stably expressed in CHO cells. The corresponding 3-isopropenyl derivatives
(+)-5a/(-)-5b, (-)-5a/(+)-5b, and some isoxazole analogs were also
tested. The binding affinities at the beta-ARs of the isoxazolinyl
amino alcohols were significantly lower than those of the corresponding
isoxazole derivatives. A stereochemical effect was observed, since
the process of molecular recognition is predominantly controlled
by the (S)-configuration of the stereogenic center located at the
5 position of the heterocycle rather than by that of the stereocenter
carrying the secondary alcohol group. On the contrary, the stereochemical
features marginally affected the efficacy response; as a matter of
fact, functional tests carried out on Delta(2)-isoxazoline derivatives
provided with a detectable binding affinity showed the overall profile
of neutral antagonists at all three beta-AR subtypes.
Synthesis of enantiopure Delta2-isoxazoline derivatives and evaluation
of their affinity and efficacy profiles at human beta-adrenergic
receptor subtypes
Dallanoce, Clelia Meroni, Giuseppe De Amici, Marco Hoffmann, Carsten
Klotz, Karl-Norbert De Micheli, Carlo Research Support, Non-U.S.
Gov't England Bioorganic & medicinal chemistry Bioorg Med Chem.
2006 Jul 1;14(13):4393-401. Epub 2006 Mar 10.
%0 Journal Article
%1 Dallanoce2006
%A Dallanoce, C.
%A Meroni, G.
%A Amici, M. De
%A Hoffmann, C.
%A Klotz, K. N.
%A Micheli, C. De
%D 2006
%J Bioorg Med Chem
%K Adrenergic Animals CHO Cricetinae Cricetulus Humans Isoxazoles/chemical Stereoisomerism beta-Antagonists/chemical beta/*drug effects synthesis/*chemistry/*pharmacology Receptor Cell
%N 13
%P 4393-401
%T Synthesis of enantiopure Delta2-isoxazoline derivatives and evaluation
of their affinity and efficacy profiles at human beta-adrenergic
receptor subtypes
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16530417
%V 14
%X The new enantiomerically pure 3-substituted-Delta(2)-isoxazolin-5-yl-ethanolamines
(+)-6a/(-)-6b, (-)-6a/(+)-6b, and (+)-7a/(-)-7b, prepared via a 1,3-dipolar
cycloaddition-based approach, were tested for their affinity at human
beta(1)-, beta(2)-, and beta(3)-adrenergic receptor (beta-AR) subtypes
stably expressed in CHO cells. The corresponding 3-isopropenyl derivatives
(+)-5a/(-)-5b, (-)-5a/(+)-5b, and some isoxazole analogs were also
tested. The binding affinities at the beta-ARs of the isoxazolinyl
amino alcohols were significantly lower than those of the corresponding
isoxazole derivatives. A stereochemical effect was observed, since
the process of molecular recognition is predominantly controlled
by the (S)-configuration of the stereogenic center located at the
5 position of the heterocycle rather than by that of the stereocenter
carrying the secondary alcohol group. On the contrary, the stereochemical
features marginally affected the efficacy response; as a matter of
fact, functional tests carried out on Delta(2)-isoxazoline derivatives
provided with a detectable binding affinity showed the overall profile
of neutral antagonists at all three beta-AR subtypes.
@article{Dallanoce2006,
abstract = {The new enantiomerically pure 3-substituted-Delta(2)-isoxazolin-5-yl-ethanolamines
(+)-6a/(-)-6b, (-)-6a/(+)-6b, and (+)-7a/(-)-7b, prepared via a 1,3-dipolar
cycloaddition-based approach, were tested for their affinity at human
beta(1)-, beta(2)-, and beta(3)-adrenergic receptor (beta-AR) subtypes
stably expressed in CHO cells. The corresponding 3-isopropenyl derivatives
(+)-5a/(-)-5b, (-)-5a/(+)-5b, and some isoxazole analogs were also
tested. The binding affinities at the beta-ARs of the isoxazolinyl
amino alcohols were significantly lower than those of the corresponding
isoxazole derivatives. A stereochemical effect was observed, since
the process of molecular recognition is predominantly controlled
by the (S)-configuration of the stereogenic center located at the
5 position of the heterocycle rather than by that of the stereocenter
carrying the secondary alcohol group. On the contrary, the stereochemical
features marginally affected the efficacy response; as a matter of
fact, functional tests carried out on Delta(2)-isoxazoline derivatives
provided with a detectable binding affinity showed the overall profile
of neutral antagonists at all three beta-AR subtypes.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Dallanoce, C. and Meroni, G. and Amici, M. De and Hoffmann, C. and Klotz, K. N. and Micheli, C. De},
biburl = {https://www.bibsonomy.org/bibtex/2bc11e0b03fd5644224b24d25ed627f2a/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {fe2b76f5472aee08c0d50222ef7ce315},
intrahash = {bc11e0b03fd5644224b24d25ed627f2a},
issn = {0968-0896 (Print) 0968-0896 (Linking)},
journal = {Bioorg Med Chem},
keywords = {Adrenergic Animals CHO Cricetinae Cricetulus Humans Isoxazoles/chemical Stereoisomerism beta-Antagonists/chemical beta/*drug effects synthesis/*chemistry/*pharmacology Receptor Cell},
month = {Jul 1},
note = {Dallanoce, Clelia Meroni, Giuseppe De Amici, Marco Hoffmann, Carsten
Klotz, Karl-Norbert De Micheli, Carlo Research Support, Non-U.S.
Gov't England Bioorganic \& medicinal chemistry Bioorg Med Chem.
2006 Jul 1;14(13):4393-401. Epub 2006 Mar 10.},
number = 13,
pages = {4393-401},
shorttitle = {Synthesis of enantiopure Delta2-isoxazoline derivatives and evaluation
of their affinity and efficacy profiles at human beta-adrenergic
receptor subtypes},
timestamp = {2010-12-14T18:22:39.000+0100},
title = {Synthesis of enantiopure Delta2-isoxazoline derivatives and evaluation
of their affinity and efficacy profiles at human beta-adrenergic
receptor subtypes},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16530417},
volume = 14,
year = 2006
}