title: 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).
abstract: 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.
authors.affiliation: School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Miharu
authors.initials: M
authors.lastname: Igarashi
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yoshimoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Masato
authors.initials: M
authors.lastname: Shimizu
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Ishizawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C520041:(25S)-26-adamantyl-25-hydroxy-2-methylene-22,23-didehydro-19,27-dinor-20-epi-vitamin D3; D018167:Receptors, Calcitriol; D002117:Calcitriol; D000218:Adamantane