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1uom

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[[Image:1uom.gif|left|200px]]
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{{STRUCTURE_1uom| PDB=1uom | SCENE= }}
{{STRUCTURE_1uom| PDB=1uom | SCENE= }}
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'''THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.'''
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===THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.===
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==Overview==
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As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C--&gt;S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.
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{{ABSTRACT_PUBMED_12825935}}
==About this Structure==
==About this Structure==
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[[Category: Transcription regulation]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 11:30:17 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 03:48:38 2008''

Revision as of 00:48, 28 July 2008

Image:1uom.png

Template:STRUCTURE 1uom

THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.

Template:ABSTRACT PUBMED 12825935

About this Structure

1UOM is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands., Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Halleux C, Kallen J, Keller H, Schlaeppi JM, Stark W, J Med Chem. 2003 Jul 3;46(14):2945-57. PMID:12825935

Page seeded by OCA on Mon Jul 28 03:48:38 2008

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