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| [[Image:1uom.gif|left|200px]] | | {{Seed}} |
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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.'''
| | ===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-->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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_12825935}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 12825935 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_12825935}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Transcription regulation]] | | [[Category: Transcription regulation]] |
| [[Category: Zinc-finger]] | | [[Category: Zinc-finger]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 11:30:17 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 03:48:38 2008'' |
