PT - JOURNAL ARTICLE AU - Yuka Inaba AU - Keiko Yamamoto AU - Nobuko Yoshimoto AU - Manabu Matsunawa AU - Shigeyuki Uno AU - Sachiko Yamada AU - Makoto Makishima TI - Vitamin D<sub>3</sub> Derivatives with Adamantane or Lactone Ring Side Chains are Cell Type-Selective Vitamin D Receptor Modulators AID - 10.1124/mol.106.032318 DP - 2007 May 01 TA - Molecular Pharmacology PG - 1298--1311 VI - 71 IP - 5 4099 - http://molpharm.aspetjournals.org/content/71/5/1298.short 4100 - http://molpharm.aspetjournals.org/content/71/5/1298.full SO - Mol Pharmacol2007 May 01; 71 AB - The vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D, which regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. We investigated the effects of three 1,25(OH)2D3 derivatives on VDR function. AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position. These vitamin D derivatives bind to VDR but do not stabilize an active cofactor conformation. In a VDR transfection assay, AD47 and LAC67b act as partial agonists and all three compounds inhibit VDR activation by 1,25(OH)2D3. The derivatives enhanced the heterodimerization of VDR with the retinoid X receptor, an effect unrelated to agonist/antagonist activity. AD47 and LAC67b weakly induced recruitment of the SRC-1 cofactor to VDR, and all three derivatives inhibited the recruitment of p160 family cofactors to VDR induced by 1,25(OH)2D3. It is noteworthy that AD47 induced DRIP205 recruitment as effectively as 1,25(OH)2D3, whereas LAC67a and LAC67b were not effective. We examined the expression of endogenous VDR target genes and the nuclear protein levels of VDR and cofactors in several cell lines, including cells derived from intestine, bone, and monocytes, and found that the vitamin D3 derivatives act as cell type-selective VDR modulators. The data indicate that side chain modification is useful in the development of VDR antagonists and tissue-selective modulators. Further elucidation of the molecular mechanisms of action of selective VDR modulators will be essential for their clinical application. The American Society for Pharmacology and Experimental Therapeutics