Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function

Abstract

5). The effects exerted via the VDR are called genomic effects, in contrast to non-genomic effects, which means that 1␣,25(OH) 2 D 3 acts within a short period without transcription of target genes (6). The VDR-mediated effects of 1␣,25(OH) 2 D 3 in vivo are well known, since there is a human disease associated with the abnormality of the VDR gene, which is called vitamin D dependence type II (7). In addition, a mouse model of the disease was generated by targeting the VDR gene and has been used the analysis of the VDR function in vivo (8, 9).The VDR consists of several functional domains such as DNA-binding and ligand-binding domains (1, 2). Heterodimerization of the VDR with retinoid X receptor (RXR) is also important for the binding to a vitamin D-responsive element (VDRE) with high affinity (1, 2, 5, 10). Ligand-dependent activation of transcription requires the extreme C-terminal portion of the VDR, which is designated as the AF-2 core domain (1,11,12). The interaction of these domains is required for the VDR to regulate the transcription of target genes.A large number of 1␣,25(OH) 2 D 3 analogues have been synthesized in an attempt to dissociate various biological activities including hypercalcemic effects, bone-forming effects, and promotion of cell differentiation (for review, see Ref. . Although this differentiation is believed to be mediated by VDR, more direct evidence is needed to establish whether TEI-9647 is an antagonist of the genomic action of vitamin D. Antagonists, if obtained, would be useful for determining whether each of the effects of 1␣,25(OH) 2 D 3 is mediated by the VDR. In addition, a potentially promising way to achieve the differential effect of vitamin D is to use analogues that antagonize particular effects elicited by vitamin D.In contrast to the case of VDR, several antagonists have been reported for other members of the nuclear hormone receptor superfamily, and have contributed to the understanding of the

Stimulation by 1,25-Dihydroxyvitamin D3 of Insulin Receptor Expression and Insulin Responsiveness for Glucose Transport in U-937 Human Promonocytic Cells.

“…Only recently an antagonist that blocks VDR-mediated actions of 1,25(OH)2D3 has been described [45,46]. Whether this antagonist, could also block the detected 1,25(OH)2D3-induced increase in IR expression and insulin action remains to be investigated.…”

1α,25-Dihydroxyvitamin D3-26,23-lactam analogues function as vitamin D receptor antagonists in human and rodent cells

“…These are the (23S)-and (23R)-25-dehydro-1α-hydroxyvitamin D 3 -26,23-lactones (TEI-9647 and TEI-9648, respectively) [4][5][6], the 25-carboxylic ester derivatives of 1α,25-(OH) 2 D 3 (ZK159222 and ZK168281) [7,8], and the (23S,25S)-N-benzyl-1α, 25- [4,6,12]. Moreover, we demonstrated that TEI-9647 prevents heterodimer complex formation between the VDR and retinoid X receptor (RXR), and recruitment of steroid receptor coactivator-1 (SRC-1) to VDR [13].…”

Highly Potent Vitamin D Receptor Antagonists: Design, Synthesis, and Biological Evaluation

“…In 1999, studies on the modification of the side-chain structure-based on a 1a,25-dihydroxyvitamin D 3 -26,23-lactone metabolite [31,32] derived from 1-led to the discovery of TEI-9647 (5) and TEI-9648 (6) (Scheme 4). [33][34][35][36][37][38][39] These two vitamin D 3 analogues, each containing an a-methylene-g-butyrolactone component in the side chain, are the first specific antagonists of VDR-mediated genomic action of 1: analogue 5, with the (23S) configuration, displays stronger antagonism than 6, with the (23R) configuration. The other class of antagonists is that of ZK-159222, which possesses long CD-ring side chains that include cyclopropane rings in their middles (see Section 5, Scheme 19).…”