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Identification of a highly potent vitamin D receptor antagonist: (25S)-26-adamantyl-25-hydroxy-2-methylene-22,23-didehydro-19,27-dinor-20-epi-vitamin D3 (ADMI3).

Igarashi M, Yoshimoto N, Yamamoto K, Shimizu M, Ishizawa M, Makishima M, DeLuca HF, Yamada S

School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.

We synthesized four new vitamin D derivatives, diastereomers at C20 and C25 of 26-adamantyl-1,25-dihydroxy-2-methylene-22,23-didehydro-19,27-dinorvitamin D3 (ADMI1-4), which have the bulky and rigid adamantane ring system at the side chain terminus. These compounds had significant VDR affinity (1/6-1/30 that of the natural hormone) but their efficacies of transactivation in transient transcription assay was low (approximately 1/10). All ADMI compounds antagonized the action of 1,25(OH)2D3 in transient transcription assay in COS-7 cells with ADMI3 (20S,25S-isomer) was the most potent (IC50, 3 nM). ADMI3 (1 microM) suppressed the endogenous CYP24A1 gene expression induced by 1,25(OH)2D3 (10 nM) in HEK293 cells to nearly control level. Thus we have identified 26-adamantyl vitamin D compound as a novel highly potent VDR antagonist/partial agonist. A docking model of ADMI3 reveals that a terminal part of the large adamantane ring crowds the H12 residues (Val318 and Phe422) and this would prevent the H12 adopting the active conformation.

Published 23 April 2007 in Arch Biochem Biophys, 460(2): 240-53.
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