Abstract：
:To investigate the molecular mechanism of vitamin D receptor (VDR) antagonists having no structurally bulky group interfering with helix 12 of the ligand-binding domain of the VDR, we have synthesized four diastereomers at C(20) and C(23) of 19-nor-1alpha-hydroxyvitamin D(3) 25-methylene-26,23-lactone bearing a 2MD-type A-ring. All four analogs showed significant VDR affinity. Transactivation was tested by using Cos7 cells and HEK293 cells. In both types of cells, LAC67a showed little transactivation potency and inhibited the activation induced by the natural hormone concentration-dependently, indicating that LAC67a works as an antagonist for the VDR in these cells. LAC67b, LAC82a and LAC82b similarly acted as VDR antagonists in Cos7 cells, but in HEK293 cells they behaved as potent VDR agonists. Docking of four lactones into the VDR-LBD, followed by structural analysis, demonstrated that each lactone lacks the hydrophobic interaction with helix12 necessary for maintaining the active conformation of the VDR, indicating that these lactones are passive-type antagonists. Furthermore, each docking structure explained the characteristic transactivation profiles of the four lactones. On the basis of our present findings, we suggest that the ligand acts as an agonist if there are appropriate coactivators in the cells to bind to the looser VDR-ligand complex, and as an antagonist if there are no such appropriate coactivators. The molecular basis of the passive antagonism is discussed in detail.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Yoshimoto N,Inaba Y,Yamada S,Makishima M,Shimizu M,Yamamoto Kdoi
10.1016/j.bmc.2007.09.017subject
Has Abstractpub_date
2008-01-01 00:00:00pages
457-73issue
1eissn
0968-0896issn
1464-3391pii
S0968-0896(07)00791-2journal_volume
16pub_type
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journal_title：Bioorganic & medicinal chemistry
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journal_title：Bioorganic & medicinal chemistry
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