title: A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor.
abstract: To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1alpha,24-dihydroxyvitamin D(3) derivatives (3-10), all having a butyl group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27-trinorvitamin D derivative 5 was a potent VDR agonist, whereas the corresponding compound 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogues with the full vitamin D(3) side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yoshimoto
authors.forename: Yuta
authors.initials: Y
authors.lastname: Sakamaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakabayashi
authors.forename: Teikichi
authors.initials: T
authors.lastname: Ikura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.forename: Masato
authors.initials: M
authors.lastname: Shimizu
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics; D047488:Retinoid X Receptors / Q000378:metabolism; D013237:Stereoisomerism; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C550367:22-butyl-1,24-dihydroxy-24,25,26-trinorvitamin D3; D000970:Antineoplastic Agents; D008024:Ligands; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D056920:Nuclear Receptor Coactivator 1; D002117:Calcitriol