2-Methylene 19-nor-25-dehydro-1alpha-hydroxyvitamin D3 26,23-lactones: synthesis, biological activities and molecular basis of passive antagonism.

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Yoshimoto N, Inaba Y, Yamada S, Makishima M, Shimizu M, Yamamoto K

2-Methylene 19-nor-25-dehydro-1alpha-hydroxyvitamin D3 26,23-lactones: synthesis, biological activities and molecular basis of passive antagonism.

Bioorg Med Chem. 2008 Jan 1;16(1):457-73. Epub 2007 Sep 14.

PubMed ID

17904370 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Calcitriol	Vitamin D3 receptor	EC 50 (nM)	0.5	N/A	N/A	Details
Calcitriol	Vitamin D3 receptor	EC 50 (nM)	1	N/A	N/A	Details