title: Effects of chemical modification of ursodeoxycholic acid on TGR5 activation.
abstract: The aim of this study is to examine the ability of the bile acid analogues obtained by chemical modification of ursodeoxycholic acid (UDCA) for TGR5 activation. Eleven UDCA analogues including 3- or 7-methylated UDCAs and amino acid conjugates were investigated as to their ability to activate TGR5 by means of the luciferase assay. It was noteworthy that 7α-methylated UDCA, namely 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid, had a significantly high affinity for and ability to activate TGR5 as compared to UDCA. Additionally, FXR activation ability of 7α-methylated UDCA was low relative to that of UDCA. However, other modification of UDCA, such as the introduction of methyl group at its C-3 position and oxidation or epimerization of hydroxyl group in the C-3 position, could not elicit such remarkable effect. The present findings would provide a useful strategy for the development of TGR5-selective agonist.
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Kure, Hiroshima 737–0112, Japan. y-iguchi@ps.hirokoku-u.ac.jp
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Iguchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Fumiteru
authors.initials: F
authors.lastname: Teraoka
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kaneko
authors.forename: Mizuho
authors.initials: M
authors.lastname: Une
mesh_terms: D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D014580:Ursodeoxycholic Acid