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).

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.